Novel genes encoding proteins having prognostic, diagnostic, preventive, therapeutic, and other uses

ABSTRACT

The invention provides isolated TANGO 239, TANGO 219, TANGO 232, TANGO 281, A236 (INTERCEPT 236), TANGO 300, TANGO 353, TANGO 393, TANGO 402, TANGO 351 and TANGO 509 nucleic acid molecules and polypeptide molecules. The invention also provides antisense nucleic acid molecules, expression vectors containing the nucleic acid molecules of the invention, host cells into which the expression vectors have been introduced, and non-human transgenic animals in which a nucleic acid molecule of the invention has been introduced or disrupted. The invention still further provides isolated polypeptides, fusion polypeptides, antigenic peptides and antibodies. Diagnostic, screening and therapeutic methods utilizing compositions of the invention are also provided.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application is a continuation-in-part of U.S. patentapplication Ser. No. 09/599,596, filed Jun. 22, 2000, which is adivisional of U.S. patent application Ser. No. 09/223,546, filed Dec.30, 1998, and a continuation-in-part of U.S. patent application Ser. No.09/471,179, filed Dec. 23, 1999, which is a continuation-in-part of U.S.patent application Ser. No. 09/223,546, filed Dec. 30, 1998.

[0002] This application is a continuation-in-part of U.S. patentapplication Ser. No. 09/474,072, filed Dec. 29, 1999, which is acontinuation-in-part of U.S. patent application Ser. No. 09/224,246,filed Dec. 30, 1998.

[0003] This application is a continuation-in-part of U.S. patentapplication Ser. No. 09/474,071, filed Dec. 29, 1999, which is acontinuation-in-part of U.S. patent application Ser. No. 09/223,094,filed Dec. 30, 1998.

[0004] This application is a continuation-in-part of U.S. patentapplication Ser. No. 09/597,993, filed Jun. 19, 2000, which is acontinuation-in-part of U.S. patent application Ser. No. 09/336,536,filed Jun. 18, 1999.

[0005] This application is a continuation-in-part of U.S. patentapplication Ser. No. 09/572,002, filed May 14, 2000, which is acontinuation-in-part of U.S. patent application Ser. No. 09/312,359,filed May 14, 1999.

[0006] This application is a continuation-in-part of U.S. patentapplication Ser. No. 09/606,565, filed Jun. 29, 2000, which is acontinuation-in-part of U.S. patent application Ser. No. 09/342,687,filed Jun. 29, 1999.

[0007] This application is a continuation-in-part of U.S. patentapplication Ser. No. 09/630,334, filed Jul. 31, 2000, which is acontinuation-in-part of U.S. patent application Ser. No. 09/365,164,filed Jul. 30, 1999.

[0008] This application is a continuation-in-part of U.S. patentapplication Ser. No. 09/665,666, filed Sep. 20, 2000, which is acontinuation-in-part of U.S. patent application Ser. No. 09/399,723,filed Sep. 20, 1999.

[0009] Each of the applications cross-referenced in this section areincorporated into this disclosure by reference in its entirety.

BACKGROUND OF THE INVENTION

[0010] Many secreted proteins, for example, cytokines and cytokinereceptors, play a vital role in the regulation of cell growth, celldifferentiation, and a variety of specific cellular responses. A numberof medically useful proteins, including erythropoietin,granulocyte-macrophage colony stimulating factor, human growth hormone,and various interleukins, are secreted proteins. Thus, an important goalin the design and development of new therapies is the identification andcharacterization of secreted and transmembrane proteins and the geneswhich encode them.

[0011] Many secreted proteins are receptors which bind a ligand andtransduce an intracellular signal, leading to a variety of cellularresponses. The identification and characterization of such a receptorenables one to identify both the ligands which bind to the receptor andthe intracellular molecules and signal transduction pathways associatedwith the receptor, permitting one to identify or design modulators ofreceptor activity, e.g., receptor agonists or antagonists and modulatorsof signal transduction.

SUMMARY OF THE INVENTION

[0012] The present invention is based, at least in part, on thediscovery of cDNA molecules which encode the TANGO 239, TANGO 219, TANGO232, TANGO 281, A236 (INTERCEPT 236), TANGO 300, TANGO 353, TANGO 393,TANGO 402, TANGO 351 and TANGO 509 proteins, all of which are eitherwholly secreted or transmembrane polypeptides.

[0013] The TANGO 353, A236 (INTERCEPT 236), TANGO 232 and TANGO 300proteins are transmembrane proteins. In an additional embodiment, thenucleic acids encoding these proteins are alternatively spliced suchthat the resulting protein products are secreted proteins.

[0014] TANGO 239 proteins are secreted proteins with homology toproteins containing MAM domains.

[0015] TANGO 219 proteins have a signal peptide and the MRNA is weaklyexpressed in heart tissues.

[0016] The TANGO 281 proteins represent proteins downregulated inmegakaryocytes that fail to express the gata-1 transcription factor (afactor critical for blood cell formation) and can, therefore, representdirect or indirect gata-1 targets.

[0017] The TANGO 393 protein are transmembrane proteins with homology toproteins containing Leucine-rich repeats (LRR) such as the Leucine-Richα-2-Glycoprotein (LRG), SLIT-1, and Platelet Glycoprotein V (GPV)precursor.

[0018] The TANGO 402 proteins are homologous to the LOX-1 protein, whichhas been associated with low density lipoprotein metabolism andatherosclerosis.

[0019] The TANGO 351 proteins are transmembrane polypeptides involved insignaling, e.g., signaling in renal cells.

[0020] The TANGO 509 proteins are transmembrane polypeptides related tobutyrophilin-like proteins and containing immunoglobulin domains.

[0021] The TANGO 239, TANGO 219, TANGO 232, TANGO 281, A236 (INTERCEPT236), TANGO 300, TANGO 353, TANGO 393, TANGO 402, TANGO 351 and TANGO509 proteins, fragments, derivatives, and variants thereof of thepresent invention are collectively referred to herein as “polypeptidesof the invention” or “proteins of the invention.” Nucleic acid moleculesencoding the polypeptides or proteins of the invention are collectivelyreferred to as “nucleic acids of the invention.”

[0022] The nucleic acids and polypeptides of the present invention areuseful as modulating agents in regulating a variety of cellularprocesses. Accordingly, in one aspect, this invention provides isolatednucleic acid molecules encoding a polypeptide of the invention or abiologically active portion thereof. The present invention also providesnucleic acid molecules which are suitable for use as primers orhybridization probes for the detection of nucleic acids encoding apolypeptide of the invention.

[0023] The invention includes fragments of any of the nucleic acidsdescribed herein wherein the fragment retains a biological or structuralfunction by which the full-length nucleic acid is characterized (e.g.,an activity, an encoded protein, or a binding capacity). The inventionfurthermore includes fragments of any of the nucleic acids describedherein wherein the fragment has a nucleotide sequence sufficiently(e.g., 50%, 60%, 70%, 80%, 85%, 90%, 95%, 98%, or 99% or greater)identical to the nucleotide sequence of the corresponding full-lengthnucleic acid that it retains a biological or structural function bywhich the full-length nucleic acid is characterized (e.g., an activity,an encoded protein, or a binding capacity).

[0024] The invention includes fragments of any of the polypeptidesdescribed herein wherein the fragment retains a biological or structuralfunction by which the full-length polypeptide is characterized (e.g., anactivity or a binding capacity). The invention furthermore includesfragments of any of the polypeptides described herein wherein thefragment has an amino acid sequence sufficiently (e.g., 50%, 60%, 70%,80%, 85%, 90%, 95%, 98%, or 99% or greater) identical to the amino acidsequence of the corresponding full-length polypeptide that it retains abiological or structural function by which the full-length polypeptideis characterized (e.g., an activity or a binding capacity).

[0025] The invention also features nucleic acid molecules which are atleast 40% (or 50%, 60%, 70%, 80%, 90%, 95%, or 98%) identical to thenucleotide sequence of any of SEQ ID NOs: 1, 3, 5, 7, 9, 11, 13, 15, 17,19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, and 43, the TANGO 239nucleotide sequence of the cDNA insert of a clone deposited on Nov. 20,1998 with the ATCC® as accession no. 98999, the TANGO 219 nucleotidesequences of cDNA insert of a clone deposited on Sep. 25, 1998 with theATCC® as accession no. 98899, the macaque TANGO 232 nucleotide sequenceof the cDNA insert of a clone deposited on Jan. 7, 1999 with the ATCC®as accession no. 207045, the human TANGO 232 nucleotide sequence of thecDNA insert of a clone deposited on Jan. 7, 1999 with the ATCC® asaccession no. 207046, the human TANGO 281 nucleotide sequence of thecDNA insert of a clone deposited on Jan. 7, 1999 with the ATCC® asaccession no. 207222, the mouse TANGO 281 nucleotide sequence of thecDNA insert of a clone deposited on Apr. 30, 1999 with the ATCC® asaccession no. PTA-224, the human A236 (INTERCEPT 236) nucleotidesequence of the cDNA insert of a clone deposited on May 7, 1999 with theATCC® as accession no. PTA-34, the TANGO 300 nucleotide sequence of thecDNA insert of a clone deposited on Jun. 30, 1999 with the ATCC® asaccession no. PTA-293, the TANGO 353 nucleotide sequence of the cDNAinsert of a clone deposited on Jun. 29, 1999 with the ATCC® as accessionno. PTA-292, the TANGO 393 nucleotide sequence of the cDNA insert of aclone deposited on Jun. 29, 1999 with the ATCC® as accession no.PTA-295, the TANGO 402 nucleotide sequence of the cDNA insert of a clonedeposited on Jun. 29, 1999 with the ATCC® as accession no. PTA-294, theTANGO 351 nucleotide sequences of cDNA inserts of clones deposited onJul. 23, 1999 with the ATCC® as accession no. PTA-424, and the TANGO 509nucleotide sequence of the cDNA insert of a clone deposited on Aug. 5,1999 with the ATCC® as accession no. PTA-438.

[0026] These deposited nucleotide sequences are hereafter individuallyand collectively referred to as “the nucleotide sequence of any of theclones deposited as ATCC® Accession numbers 98999, 98899, 207045,207046, 207222, PTA-34, PTA-224, PTA-293, PTA-292, PTA-295, PTA-294,PTA-424, and PTA-438.”

[0027] The invention features nucleic acid molecules which include afragment of at least 15 (25, 40, 60, 80, 100, 150, 200, 250, 300, 350,400, 450, 500, 600, 700, 800, 900, 1000, 1200, 1400, 1600, 1800, 2000,2200, 2400, 2600, 2800, 3000, 3500, 4000, 4500, 5000, or more)consecutive nucleotide residues of any of SEQ ID NOs: 1, 3, 5, 7, 9, 11,13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, and 43, andthe nucleotide sequence of any of the clones deposited as ATCC®Accession numbers 98999, 98899, 207045, 207046, 207222, PTA-34, PTA-34,PTA-224, PTA-293, PTA-292, PTA-295, PTA-294, PTA-424, and PTA-438, or acomplement thereof.

[0028] The invention also features nucleic acid molecules which includea nucleotide sequence encoding a protein having an amino acid sequencethat is at least 50% (or 60%, 70%, 80%, 90%, 95%, or 98%) identical tothe amino acid sequence of any of SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14,16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, or the aminoacid sequence encoded by the nucleotide sequence of any of the clonesdeposited as ATCC® Accession numbers 98999, 98899, 207045, 207046,207222, PTA-34, PTA-34, PTA-224, PTA-293, PTA-292, PTA-295, PTA-294,PTA-424, and PTA-438 or a complement thereof.

[0029] In certain embodiments, the nucleic acid molecules have thenucleotide sequence of any of SEQ ID NOs: 1, 3, 5, 7, 9, 11, 13, 15, 17,19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, and 43, and thenucleotide sequence of any of the clones deposited as ATCC® Accessionnumbers 98999, 98899, 207045, 207046, 207222, PTA-34, PTA-34, PTA-224,PTA-293, PTA-292, PTA-295, PTA-294, PTA-424, and PTA-438.

[0030] Also within the invention are nucleic acid molecules which encodea fragment of a polypeptide having the amino acid sequence of any of SEQID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34,36, 38, 40, 42, and 44, the fragment including at least 10 (12, 15, 20,25, 30, 40, 50, 75, 100, 125, 150, 200, 250, 300, 400, 500, 750, 1000 ormore) consecutive amino acid residues of any of SEQ ID NOs: 2, 4, 6, 8,10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, and44.

[0031] The invention includes nucleic acid molecules which encode anaturally occurring allelic variant of a polypeptide comprising theamino acid sequence of any of SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16,18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, and 44, wherein thenucleic acid molecule hybridizes under stringent conditions to a nucleicacid molecule having a nucleic acid sequence of any of SEQ ID NOs: 1, 3,5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41,and 43, and the nucleotide sequence of any of the clones deposited asATCC® Accession numbers 98999, 98899, 207045, 207046, 207222, PTA-34,PTA-34, PTA-224, PTA-293, PTA-292, PTA-295, PTA-294, PTA-424, andPTA-438, or a complement thereof.

[0032] Also within the invention are isolated polypeptides or proteinshaving an amino acid sequence that is at least about 50%, preferably60%, 75%, 90%, 95%, or 98% identical to the amino acid sequence of anyof SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30,32, 34, 36, 38, 40, 42, and 44.

[0033] Also within the invention are isolated polypeptides or proteinswhich are encoded by a nucleic acid molecule having a nucleotidesequence that is at least about 40%, preferably 50%, 60%, 75%, 85%, or95% identical the nucleic acid sequence encoding any of SEQ ID NOs: 2,4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40,42, and 44, and isolated polypeptides or proteins which are encoded by anucleic acid molecule consisting of the nucleotide sequence whichhybridizes under stringent hybridization conditions to a nucleic acidmolecule having the nucleotide sequence of any of SEQ ID NOs: 1, 3, 5,7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41,and 43, and the nucleotide sequence of any of the clones deposited asATCC® Accession numbers 98999, 98899, 207045, 207046, 207222, PTA-34,PTA-34, PTA-224, PTA-293, PTA-292, PTA-295, PTA-294, PTA-424, andPTA-438.

[0034] Also within the invention are polypeptides which are naturallyoccurring allelic variants of a polypeptide that includes the amino acidsequence of any of SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22,24, 26, 28, 30, 32, 34, 36, 38, 40, 42, and 44, wherein the polypeptideis encoded by a nucleic acid molecule which hybridizes under stringentconditions to a nucleic acid molecule having the nucleotide sequence ofany of SEQ ID NOs: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27,29, 31, 33, 35, 37, 39, 41, and 43, and the nucleotide sequence of anyof the clones deposited as ATCC® Accession numbers 98999, 98899, 207045,207046, 207222, PTA-34, PTA-34, PTA-224, PTA-293, PTA-292, PTA-295,PTA-294, PTA-424, and PTA-438, or a complement thereof.

[0035] The invention also features nucleic acid molecules that hybridizeunder stringent conditions to a nucleic acid molecule having thenucleotide sequence of any of SEQ ID NOs: 1, 3, 5, 7, 9, 11, 13, 15, 17,19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, and 43, and thenucleotide sequence of any of the clones deposited as ATCC® Accessionnumbers 98999, 98899, 207045, 207046, 207222, PTA-34, PTA-224, PTA-293,PTA-292, PTA-295, PTA-294, PTA-424, and PTA-438, or a complementthereof. In some embodiments, the isolated nucleic acid molecules encodea cytoplasmic, transmembrane, extracellular, or Bother domain of apolypeptide of the invention. In other embodiments, the inventionprovides an isolated nucleic acid molecule which is antisense to thecoding strand of a nucleic acid of the invention.

[0036] The invention features nucleic acid molecules of at least 550,600, 650, 700, 750, 800, 850, 900, 950, 1000, 1100, 1200, 1300, 1400,1500,1600, 1700, 1800, 1900,2000, 2100, 2150, 2200, 2250, 2300, 2350,2400, 2450, 2500, 2550, 2600, 2650, 2700, 2750, 2800, 2850, 2900, 2950,3000, 3050, 3100, 3150, 3200, 3250, 3300, 3350 or 3400 nucleotides ofthe nucleotide sequence of SEQ ID NO: 1 or 3, the nucleotide sequence ofthe TANGO 239 cDNA clone of ATCC Accession No. 98999, or a complementthereof. The invention also features nucleic acid molecules comprisingat least 25, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600,650, 700, 750, 800, 850, 900, 950, 1000, 1100, 1200, 1300, 1400, 1500,1600, 1700, 1800, 1900, 2000, 2100, 2150, 2200 or 2225 nucleotides ofnucleic acids 1 to 2227 of SEQ ID NO: 1 or 3, or a complement thereof.

[0037] The invention features nucleic acid molecules which include afragment of at least 25, 50, 100, 150, 200, 250, 300, 350, 400, 450,500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100,1150, 1200, 1250, 1300, 1350, 1400, 1450, 1500, 1550, 1600 or 1650nucleotides of the nucleotide sequence of the open reading frame (ORF)of SEQ ID NO: 1, or a complement thereof.

[0038] The invention features nucleic acid molecules which include afragment of at least 25, 50, 100, 150, 200, 250, 300, 350, 400, 450,500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100,1150, 1200, 1250, 1300, 1350, 1400, 1450, 1500, 1550, 1600, 1650, 1700,1750, 1800, 1850, 1900, 1950, 2000 or 2050 nucleotides of the nucleotidesequence of the ORF of SEQ ID NO: 3, or a complement thereof.

[0039] The invention features nucleic acid molecules of at least 25, 50,100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750,800, 850, 900, 950, 1000 or 1028 nucleotides of the nucleotide sequenceof SEQ ID NO: 5 the nucleotide sequence of a mouse TANGO 239 cDNA, or acomplement thereof.

[0040] The invention features nucleic acid molecules which include afragment of at least 25, 50, 100, 150 or 160 nucleotides of thenucleotide sequence of the ORF of SEQ ID NO: 5, or a complement thereof.

[0041] The invention features nucleic acid molecules of at least 280,300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950,1000, 1050, 1100, 1150, 1200, or 1240 nucleotides of the nucleotidesequence of SEQ ID NO: 7, the nucleotide sequence of a human TANGO 219cDNA, the nucleotide sequence of the human TANGO 219 cDNA clone of ATCCAccession No. 98899, or a complement thereof. The invention alsofeatures nucleic acid molecules comprising at least 25, 30, 35, 40, 45,50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 nucleotides of nucleicacids 1 to 2227 of SEQ ID NO: 7, or a complement thereof.

[0042] The invention features nucleic acid molecules which include afragment of at least 25, 50, 75, 100, 125, 150, 175, 200, 225, 250, 275,300, 325, 350, 375, 400, 425, or 440 nucleotides of the nucleotidesequence of the ORF of SEQ ID NO: 7, or a complement thereof.

[0043] The invention features nucleic acid molecules of at least 300,305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370,375, 380, 385, or 390 nucleotides of the nucleotide sequence of SEQ IDNO: 9, the nucleotide sequence of a mouse TANGO 219 cDNA, or acomplement thereof.

[0044] The invention features nucleic acid molecules which include afragment of at least or 300, 305, 310, 315, 320, 325, 330, 335, 340,345, 350, 355, 360 nucleotides of the nucleotide sequence of the ORF ofSEQ ID NO: 9, or a complement thereof.

[0045] The invention features nucleic acid molecules of at least 285,300, 350, 400, 450, 500, 550, 600,650,700, 750, 800, 850,900, 950,1000,1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, 1500, 1550,1600, 1650, 1700, 1750, 1800, 1850, 1900, 1925, or 1930 nucleotides ofthe nucleotide sequence of SEQ ID NO: 11, the nucleotide sequence of themacaque TANGO 232 cDNA clone of ATCC Accession No. 207045 or acomplement thereof. The invention also features nucleic acid moleculescomprising at least 25, 50, 75, 100, 125, 150, 175, 200, 225, 250, 275,300, 325, 350, 375, 400, 425, 450, 475, 500, 525, or 540 nucleotides ofnucleic acids 505 to 1050 of SEQ ID NO: 11, or a complement thereof.

[0046] The invention features nucleic acid molecules which include afragment of at least 25, 50, 75, 100,125, 150, 175, 200, 225, 250, 275,300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625,675, 700, or 710 nucleotides of the nucleotide sequence of the ORF ofSEQ ID NO: 11, or a complement thereof.

[0047] The invention features nucleic acid molecules of at least 275,300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950,1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, or 1450nucleotides of the nucleotide sequence of SEQ ID NO: 13, the nucleotidesequence of the human TANGO 232 form 1 cDNA clone of ATCC Accession No.207046, or a complement thereof. The invention also features nucleicacid molecules comprising at least 25, 50, 75, 100, 125, 150, 175, 200,225, 250, 275, 300, 325, 350, 375, 400, or 410 nucleotides of nucleicacids 1 to 415 of SEQ ID NO: 13, or a complement thereof.

[0048] The invention features nucleic acid molecules which include afragment of at least 25, 50, 75, 100, 125, 150, 175, 200, 225, 250, 275,300, 325, 350, or 360 nucleotides of the nucleotide sequence of the ORFof SEQ ID NO: 13, or a complement thereof.

[0049] The invention features nucleic acid molecules of at least 320,350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675,700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, 1000, 1025,1050, 1075, 1100, 1125, or 1130 nucleotides of the nucleotide sequenceof SEQ ID NO: 15, the nucleotide sequence of a human TANGO 232 form 2cDNA, or a complement thereof. The invention also features nucleic acidmolecules comprising at least 15, 20, 25, 30, 35, 40, 45, 50, or 55nucleotides of nucleic acids 40 to 100 of SEQ ID NO: 15, or a complementthereof.

[0050] The invention features nucleic acid molecules which include afragment of at least 320, 350, 375, 400, 425, 450, 475, 500, 525, 550,575, 600, 625, 650, 675, 700, 710, or 714 nucleotides of the nucleotidesequence of the ORF of SEQ ID NO: 15, or a complement thereof.

[0051] The invention features nucleic acid molecules of at least 325,350, 400, 450, 500, 550,600,650,700,750, 800,850,900,950,1000, 1050,1100, 1150, 1200,1250, 1300, 1350, 1400,1450, 1500, 1550,1600, 1650,1700, 1750, 1800, 1850, 1900, 1950, 2000, 2050, 2100, 2150, 2200, or2215 nucleotides of the nucleotide sequence of SEQ ID NO: 17, thenucleotide sequence of a mouse TANGO 232 cDNA, or a complement thereof.The invention also features nucleic acid molecules comprising at least25, 50, 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 360,or 370 nucleotides of nucleic acids 490 to 865 of SEQ ID NO: 17, or acomplement thereof.

[0052] The invention features nucleic acid molecules which include afragment of at least 25, 50, 75, 100, 125, 150, 175, 200, 225, 250, 275,300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625,675, 700, or 710 nucleotides of the nucleotide sequence of the ORF ofSEQ ID NO: 17, or a complement thereof.

[0053] The invention features nucleic acid molecules which include afragment of at least 50, 100, 200, 300, 400, 500, 600, 700, 800, 900,1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700 or 1800 contiguousnucleotides of the nucleotide sequence of SEQ ID NO: 19 the nucleotidesequence of an EpT281 cDNA of ATCC® Accession Number 207222, or acomplement thereof.

[0054] The invention features nucleic acid molecules which include afragment of at least 50, 100, 200, 300, 400, 500, 600, 700 or 750contiguous nucleotides of the nucleotide sequence of the ORF of SEQ IDNO: 19, or a complement thereof.

[0055] The invention features nucleic acid molecules which include afragment of at least 550, 600, 700, 800, 900, 1000, 1100, 1200, 1300,1400, 1500, 1600, 1700, 1800 or 1850 contiguous nucleotides of thenucleotide sequence of SEQ ID NO: 21 the nucleotide sequence of anEpTm281 cDNA of ATCC® patent deposit Number PTA-224, or a complementthereof.

[0056] The invention features nucleic acid molecules which include afragment of at least 50, 100, 200, 300, 400, 500, 600 or 700 contiguousnucleotides of the nucleotide sequence of the ORF of SEQ ID NO: 21, or acomplement thereof.

[0057] The invention also features nucleic acid molecules that hybridizeunder stringent conditions to a nucleic acid molecule having thenucleotide sequence of SEQ ID NOs: 19, 21, an EpTm281 cDNA of ATCC®Accession Number 207222, or a complement thereof. In other embodiments,the nucleic acid molecules are at least 710, 750, 800, 900, 1000, 1100,1200, 1300, 1400, 1500, 1600, 1700 or 1800 contiguous nucleotides inlength and hybridize under stringent conditions to a nucleic acidmolecule comprising the nucleotide sequence of SEQ ID NOs: 19, 21, anEpT281 cDNA of ATCC® Accession Number 207222, or a complement thereof.

[0058] The invention also features nucleic acid molecules that hybridizeunder stringent conditions to a nucleic acid molecule having thenucleotide sequence of SEQ ID NOs: 19, 21, an EpTm281 cDNA of ATCC®patent deposit Number PTA-224, or a complement thereof. In otherembodiments, the nucleic acid molecules are at least 580, 600, 700, 800,900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800 or 1850contiguous nucleotides in length and hybridize under stringentconditions to a nucleic acid molecule comprising the nucleotide sequenceof SEQ ID NOs: 19, 21, an EpTm281 cDNA of ATCC® patent deposit NumberPTA-224, or a complement thereof.

[0059] The invention features nucleic acid molecules comprising at least25, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 650, 700, 750,800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350,1400, 1450, 1500, 1550, 1600, 1650, 1700, 1750, 1800, 1850, 1900, or1948 nucleotides of the nucleotide sequence of SEQ ID NO: 23, thenucleotide sequence of the human TANGO A236 cDNA of ATCC® PTA-34, or acomplement thereof.

[0060] The invention features nucleic acid molecules comprising at least25, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700,750, 800, 850, 900, 950, 1000, 1050, 1100, or 1118 nucleotides of thenucleotide sequence of the ORF of SEQ ID NO: 23, or a complementthereof.

[0061] The invention features nucleic acid molecules comprising at least25, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 650, 700, 750,800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350,1400, 1450, 1500, 1550, 1600, 1650, 1700, 1750, 1800, 1850, 1900, or1945 nucleotides of the nucleotide sequence of the mouse A236 cDNA ofSEQ ID NO: 25, or a complement thereof.

[0062] The invention features nucleic acid molecules comprising at least25, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700,750, 800, 850, 900, 950, 1000, 1050, 1100, or 1115 nucleotides of thenucleotide sequence of the ORF of SEQ ID NO: 25, or a complementthereof.

[0063] The invention features nucleic acid molecules of at least 575,600, 650, 700, 800, 900, 1000, 1100 or 1200 contiguous nucleotides ofthe nucleotide sequence of SEQ ID NO: 31, the nucleotide sequence of anEpT353 cDNA of ATCC® Accession Number PTA-292, or a complement thereof.The invention also features nucleic acid molecules comprising at least20, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600 or 630contiguous nucleotides of nucleic acids 1 to 634 of SEQ ID NO: 31, or acomplement thereof.

[0064] The invention features nucleic acid molecules which include afragment of at least 150, 200, 250, 300, 350, 400, 450, 500, 550, 600,650 or 690 contiguous nucleotides of the nucleotide sequence of SEQ IDNO: 28, or a complement thereof. The invention also features nucleicacid molecules comprising at least 20, 50, 100, 150, 200, 250, 300, 350,400, 450, 500, 550 or 560 contiguous nucleotides of nucleic acids 1 to560 of the ORF of SEQ ID NO: 31, or a complement thereof.

[0065] The invention features nucleic acid molecules of at least 500,550, 600, 650, 700, 750, 800, 850, 900, 1000, 1100, 1200, 1300, 1400,1500, 1600 or 1700 contiguous nucleotides of the nucleotide sequence ofSEQ ID NO: 33, the nucleotide sequence of a human EpT393 cDNA of ATCC®Accession Number PTA-295, or a complement thereof.

[0066] The invention features nucleic acid molecules which include afragment of at least 20, 50, 100, 150, 200, 250, 300, 350, 400, 450,500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100,1150, 1200, 1250, 1300, 1350, or 1400 contiguous nucleotides of thenucleotide sequence of the ORF of SEQ ID NO: 33, or a complementthereof.

[0067] The invention features nucleic acid molecules which include afragment of at least 20, 50, 100, 150, 200, 250, 300, 350, 400, 450,500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100,1150, 1200 or 1250 contiguous nucleotides of nucleotides 1 to 1250 ofSEQ ID NO: 33, or a complement thereof.

[0068] The invention features nucleic acid molecules of at least 250,300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 1000,1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, or 1900 contiguousnucleotides of the nucleotide sequence of SEQ ID NO: 35, the nucleotidesequence of a mouse EpT393 cDNA, or a complement thereof.

[0069] The invention features nucleic acid molecules which include afragment of at least 20, 50, 100, 150, 200, 250, 300, 350, 400, 450,500, 550, 600, 650, 700, 750, 800, 850, 900, 950 or 984 contiguousnucleotides nucleotides of nucleic acids 1 to 984 of SEQ ID NO: 35, or acomplement thereof. The invention also features nucleic acid moleculeswhich include a fragment of at least 20, 50, 100, 150, 200, 250 or 292contiguous nucleotides of the nucleic acids 1177 to 1469 of SEQ ID NO:35, or a complement thereof. The invention also features nucleic acidmolecules which include a fragment of at least 20, 50, 100, 150, 200,250 or 280 contiguous nucleotides of the nucleic acids 1666 to 1946 ofSEQ ID NO: 35, or a complement thereof.

[0070] The invention features nucleic acid molecules which include afragment of at least 200, 250, 300, 350, 400, 450, 500, 550, 600, 650,700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300,1350, or 1400 contiguous nucleotide of the nucleotide sequence of theORF of SEQ ID NO: 35, or a complement thereof.

[0071] The invention features nucleic acid molecules of at least 20, 50,100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750,800, 850, 900, 1000, 1100, 1200 or 1300 contiguous nucleotides of thenucleotide sequence of SEQ ID NO: 37, the nucleotide sequence of anEpT402 cDNA of ATCC® Accession Number PTA-294, or a complement thereof.

[0072] The invention features nucleic acid molecules which include afragment of at least 20, 50, 100, 150, 200, 250, 300, 350, 400, 450,500, 550, 600 or 620 contiguous nucleotides of the nucleotide sequenceof the ORF of SEQ ID NO: 37, or a complement thereof.

[0073] The invention features nucleic acid molecules of at least 460,500, 550, 600, 650, 700, 750, 800, 850, 1000, 1100, 1200, 1300, 1400,1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600,2700, 2800, 2900, 3000, 3100, 3200, 3300 or 3340 contiguous nucleotidesof the nucleotide sequence of SEQ ID NO: 39, the nucleotide sequence ofan EpT351 cDNA of ATCC® Accession Number PTA-424, or a complementthereof. The invention also features nucleic acid molecules comprisingat least 25, 50, 100, 150, 200, 250, 300, 400, 450, 500, 550, 600, 650,700, 750, 800, 850, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700,1800, 1900, 2000, 2050 or 2071 contiguous nucleotides of nucleic acids 1to 2071 of SEQ ID NO: 39, or a complement thereof.

[0074] The invention features nucleic acid molecules which include afragment of at least 25, 50, 100, 150, 200, 250, 300, 400, 450, 500,550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1200,1300, 1400 or 1440 contiguous nucleotides of the nucleotide sequence ofthe ORF of SEQ ID NO: 39, or a complement thereof.

[0075] The invention features nucleic acid molecules of at least 475,500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1100, 1200,1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400,2500, 2600, 2700, 2800, 2900, 3000, 3100, 3200, 3300, 3400, 3500 or 3575contiguous nucleotides of the nucleotide sequence of SEQ ID NO: 41, thenucleotide sequence of an human EpT509 cDNA of ATCC® Accession NumberPTA-438, or a complement thereof. The invention also features nucleicacid molecules comprising at least 25, 50, 100, 150, 200, 250, 300, 400,450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100,1150, 1200, 1250, 1300, 1350, 1400, 1450, 1500, 1550, 1600, 1700, 1800,1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900 or 3000contiguous nucleotides of nucleic acids 1 to 3023 of SEQ ID NO: 41 or acomplement thereof.

[0076] The invention features nucleic acid molecules which include afragment of at least 25, 50, 100, 150, 200, 250, 300, 400, 450, 500,550, 600, 650, 700, 750, 800, 850 or 860 contiguous nucleotides of thenucleotide sequence of the ORF of SEQ ID NO: 41, or a complementthereof.

[0077] The invention features nucleic acid molecules of at least 265,300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950,1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, 1500, 1550,1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700,2800, 2900, 3100, 3200, 3300, 3400, 3500, 3600 or 3637 contiguousnucleotides of the nucleotide sequence of SEQ ID NO: 43, the nucleotidesequence of a mouse EpT509 cDNA or a complement thereof. The inventionalso features nucleic acid molecules comprising at least 25, 50 or 100contiguous nucleotides of nucleic acids 1 to 106 of SEQ ID NO: 43, or acomplement thereof.

[0078] The invention features nucleic acid molecules which include afragment of at least 265, 300, 350, 400, 450, 500, 550, 600, 650, 700,750, 800, 850 or 860 contiguous nucleotides of the nucleotide sequenceof the ORF of SEQ ID NO: 43, or a complement thereof. The inventionfeatures nucleic acid molecules which include a fragment of at least 25or 50 contiguous nucleotides of nucleic acids 1 to 52 of the ORF of SEQID NO: 43, or a complement thereof.

[0079] In preferred embodiments, the isolated nucleic acid moleculesencode a cytoplasmic, transmembrane, or extracellular domain of apolypeptide of the invention.

[0080] In one embodiment, the invention provides an isolated nucleicacid molecule which is antisense to the coding strand of a nucleic acidof the invention.

[0081] Another aspect of the invention provides vectors, e.g.,recombinant expression vectors, comprising a nucleic acid molecule ofthe invention. In another embodiment, the invention provides host cellscontaining such a vector or engineered to contain and/or express anucleic acid molecule of the invention. The invention also providesmethods for producing a polypeptide of the invention by culturing, in asuitable medium, a host cell of the invention containing a recombinantexpression vector encoding a polypeptide of the invention such that thepolypeptide of the invention is produced.

[0082] Another aspect of this invention features isolated or recombinantproteins and polypeptides of the invention, or modulators thereof.Preferred proteins and polypeptides possess at least one biologicalactivity possessed by the corresponding naturally-occurring humanpolypeptide. An activity, a biological activity, and a functionalactivity of a polypeptide of the invention refers to an activity exertedby a protein or polypeptide of the invention on a responsive cell asdetermined in vivo, or in vitro, according to standard techniques. Suchactivities can be a direct activity, such as an association with or anenzymatic activity on a second protein or an indirect activity, such asa cellular signaling activity mediated by interaction of the proteinwith a second protein. Thus, such activities include, e.g., (1) theability to form protein-protein interactions with proteins in thesignaling pathway of the naturally-occurring polypeptide; (2) theability to bind a ligand of the naturally-occurring polypeptide; (3) theability to bind to an intracellular target of the naturally-occurringpolypeptide.

[0083] Further activities of polypeptides of the invention include theability to modulate (this term, as used herein, includes, but is notlimited to, “stabilize”, promote, inhibit or disrupt, protein-proteininteractions (e.g., homophilic and/or heterophilic)), protein-ligandinteractions, e.g., in receptor-ligand recognition, development,differentiation, maturation, proliferation and/or activity of cellsfunction, survival, morphology, proliferation and/or differentiation ofcells of tissues in which it is expressed. Additional activities includebut are not limited to: (1) the ability to modulate cell surfacerecognition; (2) the ability to transduce an extracellular signal (e.g.,by interacting with a ligand and/or a cell-surface receptor); (3) theability to modulate a signal transduction pathway; and (4) the abilityto modulate intracellular signaling cascades (e.g., signal transductioncascades).

[0084] Other activities of polypeptides of the invention may include,e.g., (1) the ability to modulate cellular proliferation; (2) theability to modulate cellular differentiation; (3) the ability tomodulate chemotaxis and/or migration; and (4) the ability to modulatecell death.

[0085] For TANGO 219, biological activities include, the ability tomodulate the normal function, migration, proliferation, and/ordifferentiation of cells in which it is expressed (see description ofexpression data below).

[0086] For TANGO 232, biological activities include, e.g., the abilityto interact with a TANGO 232 receptor. Other activities include theability to modulate function, survival, morphology, proliferation and/ordifferentiation of cells of tissues in which it is expressed (e.g.,cells of adipose tissue). In adipose tissue, for example, TANGO 232biological activities include the ability to modulate synthesis,storage, and release of lipids, and to modulate the conversion of storedchemical energy into heat.

[0087] For TANGO 281, biological activities include, e.g., (1) theability to modulate the host immune response; (2) the ability tomodulate the proliferation, differentiation and/or activity ofhematopoeitic cells (e.g. megakaryocytes); (3) the ability to modulatethe development, differentiation, maturation, proliferation and/oractivity of pulmonary system cells; (4) the ability to modulate thedevelopment, differentiation, maturation, proliferation and/or activityintestinal cells such as M cells; (5) the ability to modulate thedevelopment, differentiation, maturation, proliferation and/or activityof stomach cells such as cells of the gastric epithelium; (6) theability to modulate intracellular signaling cascades (e.g., signaltransduction cascades); and (7) the ability to modulate plateletfunction (e.g., the promotion of platelet aggregation).

[0088] For A236, biological activities include, e.g., the ability tointeract with a A236 receptor. Other activities include the ability tomodulate function, survival, morphology, proliferation and/ordifferentiation of cells of tissues in which it is expressed. A236biological activities can include the ability to modulate aninflammatory response and the ability to modulate viral entry.

[0089] For TANGO 300, biological activities include, e.g., the abilityto interact with a TANGO 300 receptor. Other activities include theability to modulate function, survival, morphology, proliferation and/ordifferentiation of cells of tissues in which it is expressed.

[0090] For TANGO 353 or modulators thereof, biological activitiesinclude, e.g., (1) the ability to modulate development, differentiation,proliferation and/or activity of immune cells, such as lymphocytes(e.g., T cells and B cells); (2) ability to modulate cell proliferation,e.g., abnormal cell proliferation; (3) the ability to modulateintracellular signaling cascades (e.g., signal transduction cascades);and (4) the ability to modulate intercellular signaling (e.g., in theimmune system).

[0091] For TANGO 393 or modulators thereof, biological activitiesinclude, e.g., (1) the ability to modulate the proliferation,differentiation and/or activity of hypothalamus cells; (2) the abilityto modulate intracellular signaling cascades (e.g., signal transductioncascades); (3) the ability to modulate intercellular signaling; and (4)ability to modulate cell-cell interactions and/or cell-extracellularmatrix interactions.

[0092] For TANGO 402 or modulators thereof, biological activitiesinclude, e.g., (1) the ability to modulate development, differentiation,proliferation and/or activity of immune cells (e.g., leukocytes andmacrophages), endothelial cells and smooth muscle cells; (2) the abilityto modulate the host immune response; (3) the ability to modulateintracellular signaling cascades (e.g., signal transduction cascades);(4) the ability to modulate the development of organs, tissues and/orcells of the embryo and/or fetus; (5) the ability to modulate cell-cellinteractions and/or cell-extracellular matrix interactions; (6) theability to modulate atherosclerosis, e.g., the initiation andprogression of atherosclerosis; (7) the ability to modulate low-densitylipoproteins e.g., the ability to modulate levels, metabolism and/orcellular uptake of oxidized low-density lipoprotein (Ox-LDL), theability to bind to Ox-LDL, and the ability to modulate Ox-LDL activityin cells; (8) the ability to modulate atherogenesis; and (9) the abilityto modulate inflammatory functions e.g. by modulating leukocyte adhesionto extracellular matrix and/or endothelial cells; (10) the ability tobind proteins, e.g., lipoproteins, e.g., low-density lipoproteins, e.g.,oxidatively modified low-density lipoproteins; (11) the ability tomodulate internalization of proteins, e.g., lipoproteins, e.g.,low-density lipoproteins, e.g., oxidatively modified low-densitylipoproteins; (12) the ability to modulate degradation, e.g.,proteolytic degradation, of proteins, e.g., lipoproteins, e.g.,low-density lipoproteins, e.g., oxidatively modified low-densitylipoproteins; (13) the ability to modulate, e.g., increase, uptake ofproteins, e.g., lipoproteins, e.g., low-density lipoproteins, e.g.,oxidatively modified low-density lipoproteins, by cells, e.g.,macrophages and muscle cells, e.g., smooth muscle cells; (14) theability to modulate, e.g., prevent, lipid deposition, e.g., in arteries,and thus modulate, e.g., prevent, intimal thickening; (15) the abilityto modulate, e.g., induce or prevent, changes in cells, e.g.,transformation of cells (e.g., macrophages and smooth muscle cells) intofoam cells and functional alteration of cells (e.g., endothelial cells,e.g., intimal neovascular endothelial cells); (16) the ability to bindand phagocytose cells, e.g., aged and apoptotic cells; (17) the abilityto remove debris, e.g., apoptotic cells, from blood vessel walls; (18)the ability to modulate homeostasis, e.g., vascular homeostasis, e.g.,by modulating, e.g., preventing the impairment of, nitric oxideproduction; (19) the ability to modulate, e.g., inhibit, the expressionof molecules, e.g., adhesion molecules (e.g., leukocyte adhesionmolecules) and growth factors (e.g., smooth-muscle growth factors); (20)the ability to alter, e.g., increase, expression in response to stimuli,e.g., TNF, shear stress, and pathophysiological stimuli relevant todisorders (e.g., atherosclerosis and inflammation); (21) the ability toform, e.g., stabilize, promote, facilitate, inhibit, or disrupt, cell tocell and cell to blood product interaction, e.g., between leukocytes andplatelets or leukocytes and vascular endothelial cells; and (22) theability to recognize large molecules, e.g., carbohydrates.

[0093] For TANGO 351 or modulators thereof, biological activitiesinclude, e.g., (1) the ability to modulate the development,differentiation, morphology, migration or chemotaxis, proliferationand/or activity of kidney cells and the kidney; (2) the ability tomodulate, protein-protein interactions (e.g., homophilic and/orheterophilic), and protein-ligand interactions, e.g., in receptor-ligandrecognition; (3) ability to modulate cell-cell interactions and/orcell-extracellular matrix interactions; (4) the ability to modulateintracellular signaling cascades (e.g., signal transduction cascades);(5) the ability to modulate the development of organs, tissues and/orcells in an embryo and/or fetus.

[0094] For TANGO 509 or modulators thereof, biological activitiesinclude, e.g., (1) the ability to modulate the development,differentiation, morphology, migration or chemotaxis, proliferationand/or activity of mammary cells, e.g., mammary epithelial cells; (2)the ability to modulate the development and progression of cellproliferative disorders such as cancer (e.g. breast or breast-associatedcancer); (3) the ability to modulate, protein-protein interactions(e.g., homophilic and/or heterophilic), and protein-ligand interactions,e.g., in receptor-ligand recognition; (4) ability to modulate cell-cellinteractions and/or cell-extracellular matrix interactions; (5) theability to modulate mammary processes (e.g., milk secretion or fatsecretion in milk); (6) the ability to modulate intracellular signalingcascades (e.g., signal transduction cascades); (7) the ability tomodulate intercellular signaling (e.g., hormonal signals to secretemilk); (8) the ability to modulate the development of embryonic organs,tissues and/or cells; (9) the ability to modulate the development,differentiation, morphology, migration or chemotaxis, proliferationand/or activity of immune cells (e.g., B-lymphocytes, T-lymphocytes andmonocytes); (10) the ability to modulate hematopoietic processes (e.g.,immune response); (11) the ability to modulate MHC class I recognitionand binding; (12) the ability to modulate ligand-receptor interactionsin proteins with immunoglobulin domains; (13) the ability to modulateimmunoglobulin binding to antigens; (14) the ability to modulatelymphocyte selection such as modulation of B-cell receptor or T-cellreceptor stimulation in developing lymphocytes, e.g., through modulationof interaction of antigens with the immunoglobulin domain(s) of theimmune cell's antigen receptors; (15) the ability to modulateimmunoglobulin production; and (16) the ability to modulate cellkilling, such as, the ability to modulate production of cytokines oractivation of cytotoxic T-cell killing.

[0095] In one embodiment, a polypeptide of the invention has an aminoacid sequence sufficiently identical to an identified domain of apolypeptide of the invention. As used herein, the term “sufficientlyidentical” refers to a first amino acid or nucleotide sequence whichcontains a sufficient or minimum number of identical or equivalent(e.g., with a similar side chain) amino acid residues or nucleotides toa second amino acid or nucleotide sequence such that the first andsecond amino acid or nucleotide sequences have or encode a commonstructural domain and/or common functional activity. For example, aminoacid or nucleotide sequences which contain or encode a common structuraldomain having about 60% identity, preferably about 65% identity, morepreferably about 75%, 85%, 95%, 98% or more identity are defined hereinas sufficiently identical.

[0096] In one embodiment, the isolated polypeptides of the inventioninclude at least one or more of the following domains: a signalsequence, an extracellular domain, a transmembrane domain and anintracellular or cytoplasmic domain.

[0097] In another embodiment, the isolated polypeptide of the inventionlacks both a transmembrane and cytoplasmic domain. In yet anotherembodiment, a polypeptide of the invention lacks both a transmembraneand a cytoplasmic domain and is soluble under physiological conditions.In yet another embodiment, a polypeptide of the invention is fused toeither heterologous sequences, or is fused in two or more repeats of adomain, e.g., binding or enzymatic, and is soluble under physiologicalconditions.

[0098] The polypeptides of the present invention, or biologically activeportions thereof, can be operably linked to a heterologous amino acidsequence to form fusion proteins. The invention further featuresantibody substances that specifically bind a polypeptide of theinvention, such as monoclonal or polyclonal antibodies, antibodyfragments, and single-chain antibodies. In addition, the polypeptides ofthe invention or biologically active portions thereof can beincorporated into pharmaceutical compositions, which optionally includepharmaceutically acceptable carriers. These antibody substances can bemade, for example, by providing the polypeptide of the invention to animmuno-competent vertebrate and thereafter harvesting blood or serumfrom the vertebrate.

[0099] In another aspect, the present invention provides methods fordetecting the presence, activity or expression of a polypeptide of theinvention in a biological sample by contacting the biological samplewith an agent capable of detecting an indicator of the presence,activity or expression such that the presence activity or expression ofa polypeptide of the invention is detected in the biological sample.

[0100] In another aspect, the invention provides methods for modulatingactivity of a polypeptide of the invention comprising contacting a cellwith an agent that modulates (e.g., inhibits or stimulates) the activityor expression of a polypeptide of the invention such that activity orexpression in the cell is modulated. In one embodiment, the agent is anantibody that specifically binds to a polypeptide of the invention. Inanother embodiment, the agent is a fragment of a polypeptide of theinvention or a nucleic acid molecule encoding such a polypeptidefragment.

[0101] In another embodiment, the agent modulates expression of apolypeptide of the invention by modulating transcription, splicing, ortranslation of an mRNA encoding a polypeptide of the invention. In yetanother embodiment, the agent is a nucleic acid molecule having anucleotide sequence that is antisense to the coding strand of an mRNAencoding a polypeptide of the invention.

[0102] The present invention also provides methods to treat a subjecthaving a disorder characterized by aberrant activity of a polypeptide ofthe invention or aberrant expression of a nucleic acid of the inventionby administering an agent which is a modulator of the activity of apolypeptide of the invention or a modulator of the expression of anucleic acid of the invention to the subject. In one embodiment, themodulator is a protein of the invention. In another embodiment, themodulator is a nucleic acid of the invention. In other embodiments, themodulator is a polypeptide (e.g., an antibody or a fragment of apolypeptide of the invention), a peptidomimetic, or other small molecule(e.g., a small organic molecule).

[0103] The present invention also provides diagnostic assays foridentifying the presence or absence of a genetic lesion or mutationcharacterized by at least one of: (i) aberrant modification or mutationof a gene encoding a polypeptide of the invention, (ii) mis-regulationof a gene encoding a polypeptide of the invention, and (iii) aberrantpost-translational modification of the invention wherein a wild-typeform of the gene encodes a protein having the activity of thepolypeptide of the invention.

[0104] In another aspect, the invention provides a method foridentifying a compound that binds to or modulates the activity of apolypeptide of the invention. In general, such methods entail measuringa biological activity of the polypeptide in the presence and absence ofa test compound and identifying those compounds which alter the activityof the polypeptide.

[0105] The invention also features methods for identifying a compoundwhich modulates the expression of a polypeptide or nucleic acid of theinvention by measuring the expression of the polypeptide or nucleic acidin the presence and absence of the compound.

[0106] Other features and advantages of the invention will be apparentfrom the following detailed description and claims.

BRIEF DESCRIPTION OF THE DRAWINGS

[0107]FIG. 1 depicts the cDNA sequence of human TANGO 239, form 1 (SEQID NO: 1) and predicted amino acid sequence of TANGO 239, form 1 (SEQ IDNO: 2). The open reading frame extends from nucleotide 344 to 1990 ofSEQ ID NO: 1.

[0108]FIG. 2 depicts a hydropathy plot of a human TANGO 239. Relativelyhydrophobic residues are above the dashed horizontal line, andrelatively hydrophilic residues are below the dashed horizontal line.The cysteine residues (cys) and potential N-glycosylation sites (Ngly)are indicated by short vertical lines just below the hydropathy trace.

[0109]FIG. 3 depicts the alignment of amino acids 24 to 169, amino acids170 to 329 and amino acids 340 to 498 of TANGO 239 (SEQ ID NO: 2) andthe MAM consensus sequence. In these alignments, an uppercase letterbetween the two sequences indicates an exact match, and a (+) indicatesa conservative amino acid substitution.

[0110]FIG. 4 depicts the cDNA sequence of human TANGO 239, form 2 (cloneAthxe3b8)(SEQ ID NO: 3) and predicted amino acid sequence of human TANGO239, form 2 (clone Athxe3b8)(SEQ ID NO: 4). The open reading frameextends from nucleotide 344 to 2401 of SEQ ID NO: 3.

[0111]FIG. 5 depicts the cDNA sequence of mouse TANGO 239 (SEQ ID NO: 5)and predicted amino acid sequence of mouse TANGO 239 (SEQ ID NO: 6). Theopen reading frame extends from nucleotide 209 to 370 of SEQ ID NO: 5.

[0112]FIG. 6 depicts the cDNA sequence of human TANGO 219 (SEQ ID NO: 7)and the predicted amino acid sequence of TANGO 219 (SEQ ID NO: 8). Theopen reading frame extends from nucleotide 106 to nucleotide 552 of SEQID NO: 7.

[0113]FIG. 7 depicts a hydropathy plot of human TANGO 219, the detailsof which are described herein. The amino acid sequence of TANGO 219appears beneath the plot.

[0114]FIG. 8 depicts the eDNA sequence of mouse TANGO 219 (SEQ ID NO: 9)and the predicted amino acid sequence of TANGO 219 (SEQ ID NO: 10). Theopen reading frame comprises from nucleotide 2 to 370 nucleotide of SEQID NO: 9.

[0115]FIG. 9 depicts the CDNA sequence (SEQ ID NO: 11) and the predictedamino acid sequence (SEQ ID NO: 12) of macaque TANGO 232. The openreading frame extends from nucleotide 96 to nucleotide 809 of SEQ ID NO:11.

[0116]FIG. 10 depicts a hydropathy plot of macaque TANGO 232, thedetails of which are described herein.

[0117]FIG. 11 depicts an alignment of a portion of the macaque TANGO 232amino acid sequence (amino acids 1-132 of SEQ ID NO: 12) with atranslation of a rabbit nucleotide sequence (GenBank Accession NumberC83084; SEQ ID NO: 45) and a mouse nucleotide sequence (clone jtmoa3lfl;SEQ ID NO: 18). This alignment defines a cysteine-rich domain that isconserved among these three species. The arrows point to the conservedcysteine residues at positions 49, 54, 61, 72, and 74 of SEQ ID NO: 12.An additional cysteine residue at position 106 is conserved in themacaque and rabbit sequences.

[0118]FIG. 12 depicts the cDNA sequence (SEQ ID NO: 13) and thepredicted amino acid sequence (SEQ ID NO: 14) of human TANGO 232,form 1. The open reading frame comprises nucleotide 1 to nucleotide 366of SEQ ID NO: 13.

[0119]FIG. 13 depicts an alignment of a portion of the cDNA sequence ofmacaque (nucleotides 424-1937 of SEQ ID NO: 11) and human (SEQ ID NO:13) TANGO 232, form 1 and shows that there is 83.4% identity between thetwo sequences.

[0120]FIG. 14 depicts an alignment of a portion of the amino acidsequence of macaque (amino acids 93-238 of SEQ ID NO: 12) and human (SEQID NO: 14) TANGO 232 and shows that there is 94.9% identity between thetwo sequences.

[0121]FIG. 15 depicts the cDNA sequence of human TANGO 232 (SEQ ID NO:15) and predicted amino acid sequence of human TANGO 232 (SEQ ID NO:16). The open reading frame extends from nucleotide 110 to 823 of SEQ IDNO: 15.

[0122]FIG. 16 depicts the cDNA sequence of mouse TANGO 232 (SEQ ID NO:17) and predicted amino acid sequence of mouse TANGO 232 (SEQ ID NO:18). The open reading frame extends from nucleotide 79 to 795 of SEQ IDNO: 17.

[0123]FIG. 17 depict the cDNA sequence of human TANGO 281 (SEQ ID NO:19) and the predicted amino acid sequence of human TANGO 281 (SEQ ID NO:20). The open reading frame extends from nucleotide 65 to nucleotide 799of SEQ ID NO: 19.

[0124]FIG. 18 depicts a hydropathy plot of human TANGO 281, the detailsof which are described herein. The dashed vertical line separates thesignal sequence (amino acids 1 to 38 of SEQ ID NO: 20) on the left fromthe mature protein (amino acids 39 to 245 of SEQ ID NO: 20) on theright.

[0125]FIG. 19 depicts an alignment of the amino acid sequence ofphotosystem II 10 kD phosphoprotein domain (SEQ ID NO: 46; GenBankAccession Number PF00737) and the amino acid sequence 97 to 146 of humanTANGO 281 (SEQ ID NO: 20). This alignment was performed using the ALIGNalignment program with a PAM120 scoring matrix, a gap length penalty of12, and a gap penalty of 4.

[0126]FIG. 20 depict the cDNA sequence of mouse TANGO 281 (SEQ ID NO:21) and the predicted amino acid sequence of mouse TANGO 281 (SEQ ID NO:22). The open reading frame extends from nucleotide 90 to nucleotide 728of SEQ ID NO: 21.

[0127]FIG. 21 depicts a hydropathy plot of mouse TANGO 281, the detailsof which are described herein. The dashed vertical line separates thesignal sequence (amino acids 1 to 26 of SEQ ID NO: 22) on the left fromthe mature protein (amino acids 27 to 213 of SEQ ID NO: 22) on theright.

[0128]FIG. 22 depicts an alignment of the amino acid sequence of humanTANGO 281 (SEQ ID NO: 20) and the amino acid sequence of mouse TANGO 281(SEQ ID NO: 22). The alignment demonstrates that the amino acidsequences of human and mouse TANGO 281 are 66.5% identical. Thisalignment was performed using the ALIGN program with a PAM120 scoringmatrix, a gap length penalty of 12 and a gap penalty of 4.

[0129]FIG. 23 depict the cDNA sequence (SEQ ID NO: 23) and the predictedamino acid sequence (SEQ ID NO: 24) of human A236. The open readingframe extends from nucleotide 314 to nucleotide 1432 of SEQ ID NO: 23.

[0130]FIG. 24 depicts a hydropathy plot of human A236, the details ofwhich are described herein.

[0131]FIG. 25 depicts an alignment of the immunoglobulin domains,residues 28 to 113 and 146 to 210, of human A236 with a consensusimmunoglobulin domain.

[0132]FIG. 26 depicts the cDNA sequence (SEQ ID NO: 25) and thepredicted amino acid sequence (SEQ ID NO: 26) of mouse A236. The openreading frame extends from nucleotide to nucleotide 304 to 1422 of SEQID NO: 25.

[0133]FIG. 27 depict an alignment of the open reading frames of humanA236 (SEQ ID NO: 23; bottom sequence) and mouse A236 (SEQ ID NO: 25; topsequence).

[0134]FIG. 28 depicts an alignment of the amino acid sequences of humanA236 (SEQ ID NO: 24; bottom sequence) and mouse A236 (SEQ ID NO: 26; topsequence).

[0135]FIG. 29 depicts a hydropathy plot of mouse A236, the details ofwhich are described herein.

[0136]FIG. 30 depicts the cDNA sequence (SEQ ID NO: 27) and thepredicted amino acid sequence (SEQ ID NO: 28) of human TANGO 300. Theopen reading frame extends from nucleotide 31 to nucleotide 1113 of SEQID NO: 27.

[0137]FIG. 31 depicts a hydropathy plot of human TANGO 300, the detailsof which are described herein.

[0138]FIG. 32 depicts the cDNA sequence (SEQ ID NO: 29) and thepredicted amino acid sequence (SEQ ID NO: 30) of mouse TANGO 300. Theopen reading frame extends from nucleotide 41 to nucleotide 1195 of SEQID NO: 29.

[0139]FIG. 33 depicts a hydropathy plot of mouse TANGO 300, the detailsof which are described herein.

[0140]FIG. 34 depicts an alignment of the nucleotide sequence of theopen reading frame (ORF) of human TANGO 300 (SEQ ID NO: 27) and thenucleotide sequence of the ORF of mouse TANGO 300 (SEQ ID NO: 29). Thisalignment was created using BESTFIT (BLOSUM 62 scoring matrix; gap openpenalty of 12; frame shift penalty of 5; gap extend penalty of 4). Inthis alignment, the sequences are 77.7% identical.

[0141]FIG. 35 depicts an alignment of the amino acid sequence of humanTANGO 300 (SEQ ID NO: 28) and the amino acid sequence of mouse TANGO 300(SEQ ID NO: 30). This alignment was created using BESTFIT (BLOSUM 62scoring matrix; gap open penalty of 12; frame shift penalty of 5; gapextend penalty of 4). In this alignment, the sequences are 69.6%identical.

[0142]FIG. 36 depicts the cDNA sequence of human TANGO 353 (SEQ ID NO:31) and the predicted amino acid sequence of human TANGO 353 (SEQ ID NO:32). The open reading frame of human TANGO 353 extends from nucleotide76 to nucleotide 765 of SEQ ID NO: 31.

[0143]FIG. 37 depicts a hydropathy plot of human TANGO 353, the detailsof which are described herein. The dashed vertical line separates thesignal sequence (amino acids 1 to 14 of SEQ ID NO: 32) on the left fromthe mature protein (amino acids 15 to 230 of SEQ ID NO: 32) on theright.

[0144]FIG. 38 depicts the cDNA sequence of human TANGO 393 (SEQ ID NO:33) and the predicted amino acid sequence of human TANGO 393 (SEQ ID NO:34). The open reading frame extends from nucleotide 40 to nucleotide1458 (SEQ ID NO: 33).

[0145]FIG. 39 depicts a hydropathy plot of human TANGO 393, the detailsof which are described herein. The dashed vertical line separates thesignal sequence (amino acids 1 to 26 of SEQ ID NO: 34) on the left fromthe mature protein (amino acids 27 to 473 of SEQ ID NO: 34) on theright.

[0146]FIG. 40 depicts the cDNA sequence of mouse TANGO 393 (SEQ ID NO:35) and the predicted amino acid sequence of mouse TANGO 393 (SEQ ID NO:36). The open reading frame extends from nucleotide 226 to nucleotide1644 (SEQ ID NO: 35).

[0147]FIG. 41 depicts a hydropathy plot of mouse TANGO 393, the detailsof which are described herein. The dashed vertical line separates thesignal sequence (amino acids 1 to 26 of SEQ ID NO: 36) on the left fromthe mature protein (amino acids 27 to 473 of SEQ ID NO: 36) on theright.

[0148]FIG. 42 depicts an alignment of the open reading frames of humanTANGO 393 (SEQ ID NO: 33) and mouse TANGO 393 (SEQ ID NO: 35)demonstrating an identity of 82.8%. The algorithm used to align thesequences was the ALIGN program which calculates a global alignment oftwo sequences. (Version 2.0u, Myers and Miller, 1989)

[0149]FIG. 43 depicts an alignment of the immature proteins of humanTANGO 393 (SEQ ID NO: 34) and mouse TANGO 393 (SEQ ID NO: 36)demonstrating an identity of 89.2%. The algorithm used to align thesequences was the ALIGN program which calculates a global alignment oftwo sequences. (Version 2.0 u, Myers and Miller, 1989)

[0150]FIG. 44 depicts the cDNA sequence of human TANGO 402 (SEQ ID NO:37) and the predicted amino acid sequence of human TANGO 402 (SEQ ID NO:38). The open reading frame of human TANGO 402 extends from nucleotide87 to nucleotide 707 of SEQ ID NO: 37.

[0151]FIG. 45 depicts a hydropathy plot of human TANGO 402, the detailsof which are described herein. The dashed vertical line separates thesignal sequence (amino acids 1 to 50 of SEQ ID NO: 38) on the left fromthe mature protein (amino acids 51 to 207 of SEQ ID NO: 38) on theright.

[0152]FIG. 46 depicts an alignment of the amino acid sequence of humanTANGO 402 (SEQ ID NO: 38) and the amino acid sequence of human LOX-1(SEQ ID NO: 47; Accession Number AB010710). The alignment demonstratesthat the amino acid sequences of human TANGO 402 and human LOX-1 are25.1% identical. This alignment was performed using the ALIGN programwith a PAM120 scoring matrix, a gap length penalty of 12 and a gappenalty of 4.

[0153]FIG. 47 depicts an alignment of the nucleotide sequences of theopen reading frames of human TANGO 402 (SEQ ID NO: 44) and human LOX-1(SEQ ID NO: 47; Accession Number AB010710). The alignment of the openreading frame of human TANGO 402 and that of human LOX-1 demonstratesthat those two coding regions are 42.0% identical. An alignmentdemonstrates that the nucleotide sequences of the cDNA of human TANGO402 and human LOX-1 are 44.0% identical. The alignments were performedusing the ALIGN program with a PAM120 scoring matrix, a gap lengthpenalty of 12, and a gap penalty of 4. A (:) between nucleotidesrepresents an exact match, a (.) between nucleotides represents a C to Tor T to C change, or an A to G or G to A change.

[0154]FIG. 48 depicts the cDNA sequence of human TANGO 351 (SEQ ID NO:39) and the predicted amino acid sequence of human TANGO 351 (SEQ ID NO:40). The open reading frame of human TANGO 351 extends from nucleotides143 to 1588 of SEQ ID NO: 39.

[0155]FIG. 49 depicts a hydropathy plot of human TANGO 351, the detailsof which are described herein. The dashed vertical line separates thesignal sequence (amino acids 1 to 24 of SEQ ID NO: 40 on the left fromthe mature protein (amino acids 25 to 482 of SEQ ID NO: 40) on theright.

[0156]FIG. 50 depicts the cDNA sequence of human TANGO 509 (SEQ ID NO:41) and the predicted amino acid sequence of human TANGO 509 (SEQ ID NO:42). The open reading frame of human TANGO 509 extends from nucleotides59 to 928 of SEQ ID NO: 41.

[0157]FIG. 51 depicts a hydropathy plot of human TANGO 509, the detailsof which are described herein. The dashed vertical line separates thesignal sequence (amino acids 1 to 18 of SEQ ID NO: 42) on the left fromthe mature protein (amino acids 19 to 290 of SEQ ID NO: 42) on theright.

[0158]FIG. 52 depicts an alignment of the human TANGO 509 amino acidsequence (SEQ ID NO: 42) with the butyrophilin-like protein amino acidsequence (SEQ ID NO: 48; Accession Number AF142780). The alignment showsthat there is a 33.0% overall amino acid sequence identity between humanTANGO 509 and the butyrophilin-like protein. This alignment wasperformed using the ALIGN alignment program with a PAM120 scoringmatrix, a gap length penalty of 12, and a gap penalty of 4.

[0159]FIG. 53 depicts the cDNA sequence of mouse TANGO 509 (SEQ ID NO:43) and the predicted amino acid sequence of mouse TANGO 509 (SEQ ID NO:44). The open reading frame of mouse TANGO 509 extends from nucleotide49 to 918 of SEQ ID NO: 43.

[0160]FIG. 54 depicts a hydropathy plot of mouse TANGO 509, the detailsof which are described herein. The dashed vertical line separates thesignal sequence (amino acids 1 to 18 of SEQ ID NO: 44) on the left fromthe mature protein (amino acids 19 to 290 of SEQ ID NO: 44) on theright.

[0161]FIG. 55 depicts an alignment of the mouse TANGO 509 amino acidsequence (SEQ ID NO: 44) with the butyrophilin-like protein amino acidsequence (SEQ ID NO: 48; Accession Number AF142780). The alignment showsthat there is a 31.9% overall amino acid sequence identity between mouseTANGO 509 and the butyrophilin-like protein. This alignment wasperformed using the ALIGN alignment program with a PAM120 scoringmatrix, a gap length penalty of 12, and a gap penalty of 4.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0162] The TANGO 239, TANGO 219, TANGO 232, TANGO 281, A236 (INTERCEPT236), TANGO 300, TANGO 353, TANGO 393, TANGO 402, TANGO 351 and TANGO509 proteins and nucleic acid molecules comprise families of moleculeshaving certain conserved structural and functional features among familymembers. Examples of conserved structural domains include signalsequence (or signal peptide or secretion signal), transmembrane domains,cytoplasmic domains and extracellular domains.

[0163] As used herein, the terms “family” or “families” are intended tomean two or more proteins or nucleic acid molecules having a commonstructural domain and having sufficient amino acid or nucleotidesequence identity as defined herein. Family members can be from eitherthe same or different species. For example, a family can comprise two ormore proteins of human origin, or can comprise one or more proteins ofhuman origin and one or more of non-human origin. Members of the samefamily may also have common structural domains.

[0164] As used herein, a “signal sequence” includes a peptide of atleast about 15 or 20 amino acid residues in length which occurs at theN-terminus of secretory and membrane-bound proteins and which containsat least about 70% hydrophobic amino acid residues such as alanine,leucine, isoleucine, phenylalanine, proline, tyrosine, tryptophan, orvaline. In a preferred embodiment, a signal sequence contains at leastabout 10 to 40 amino acid residues, preferably about 19-34 amino acidresidues, and has at least about 60-80%, more preferably at least about65-75%, and more preferably at least about 70% hydrophobic residues. Asignal sequence serves to direct a protein containing such a sequence toa lipid bilayer. A signal sequence is usually cleaved during processingof the mature protein.

[0165] As used herein, a “transmembrane domain” refers to an amino acidsequence having at least about 25 to 40 amino acid residues in lengthand which contains hydrophobic amino acid residues such as alanine,leucine, isoleucine, phenylalanine, proline, tyrosine, tryptophan, orvaline. In a preferred embodiment, a transmembrane domain contains atleast about 25 to 40 amino acid residues, preferably about 25-30 aminoacid residues, and has at least about 60-80% hydrophobic residues.

[0166] As used herein, a “cytoplasmic loop” includes an amino acidsequence located within a cell or within the cytoplasm of a cell and istypically associated with a transmembrane protein segment which extendsthrough the cellular membrane to the extracellular region.

[0167] As used herein, an “extracellular domain” is a protein structuraldomain which is part of a transmembrane protein and resides outside thecell membrane, or is extracytoplasmic. A protein which has more than onetransmembrane domain likewise has more than one extracellular domain.When located at the N-terminal domain the extracellular domain isreferred to herein as an “N-terminal extracellular domain”. As usedherein, an “N-terminal extracellular domain” includes an amino acidsequence. The N-terminal extracellular domain can be at least 10 aminoacids in length or more, about 25, about 50, about 100, about 150, about250, about 300, about 350, about 400, about 450, about 500, about 550,about 600, about 650, about 700, or more than about 750 amino acids.

[0168] The N-terminal extracellular domain is located outside of a cellor is extracellular. The C-terminal amino acid residue of a “N-terminalextracellular domain” is adjacent to an N-terminal amino acid residue ofa transmembrane domain in a naturally-occurring protein. Preferably, theN-terminal extracellular domain is capable of interacting (e.g., bindingto) with an extracellular signal, for example, a ligand (e.g., aglycoprotein hormone) or a cell surface receptor (e.g., an integrinreceptor). Most preferably, the N-terminal extracellular domain mediatesa variety of biological processes, for example, protein-proteininteractions, signal transduction and/or cell adhesion.

[0169] TANGO 239

[0170] In one aspect, the present invention is based on the discovery ofcDNA molecules which encode a novel family of proteins referred toherein as TANGO 239 proteins. The TANGO 239 proteins and nucleic acidmolecules comprise a family of molecules having certain conservedstructural and functional features. For example, the present inventionfeatures TANGO 239 proteins having at least one, preferably two orthree, MAM domain(s). The MAM domain is associated with various adhesiveproteins and as such is likely to have adhesive function. Within MAMdomains are conserved cysteine residues which play a role in theadhesion of a MAM domain to other proteins. As used herein, a MAM domainrefers to an amino acid sequence of about 130 to about 170, preferablyabout 140 to 165, and more preferably about 145, 146 to 159 or 160 aminoacids in length.

[0171] Conserved amino acid motifs, referred to herein as “consensuspatterns” or “signature patterns”, can be used to identify TANGO 239family members having a MAM domain. For example, the following signaturepattern can be used to identify TANGO 239 family members: G-x-[LIVMFY](2) x(3) [STA] x(10,11)[LV]-x(4,6)-[LIVMF]-x(6,7)-C-[LIVM]-x(3)-[LIVMFY]-x(3,4)-[GSC]. Thesignatu patterns or consensus patterns described herein are describedaccording to the following designations: all amino acids are indicatedaccording to their universal single letter designation; “x” designatesany amino acid; x(n) designates “n” number of amino acids, e.g., x(2)designates any two amino acids, e.g., x(6,7) designates any six to sevenamino acids; and, amino acids in brackets indicates any one of the aminoacids within the brackets, e.g., [STA] indicates any of one of either S(serine), T (threonine) or A (alanine). TANGO 239 has such a signaturepattern at about amino acids 50 to 90, amino acids 215 to 256 and/oramino acids 380 to 420 of SEQ ID NO: 2.

[0172] A MAM domain further contains at least about 2 to 6, preferably,3 to 5, more preferably 4 conserved cysteine residues. By alignment of aTANGO 239 family member with a MAM consensus sequence, conservedcysteine residues can be found. For example, as shown in FIG. 3, thereis a first cysteine residue in the MAM consensus sequence thatcorresponds to a cysteine residue at amino acid 26 of the first MAMdomain of TANGO 239 (SEQ ID NO: 2); there is a second cysteine residuein the MAM consensus sequence that corresponds to a cysteine residue atamino acid 33 of TANGO 239 (SEQ ID NO: 2); there is a third cysteineresidue in the MAM consensus sequence that corresponds to a cysteineresidue at amino acid 80 of TANGO 239 (SEQ ID NO: 2); and/or there is afourth cysteine residue in the MAM consensus sequence that correspondsto a cysteine residue at amino acid 167 of TANGO 239 (SEQ ID NO: 2). Inaddition, conserved cysteine residues can be found at amino acids 170,178, 246 and/or 327 of the second MAM domain of TANGO 239 (SEQ ID NO:2); and at amino acids 342, 349, 411 and/or 496 of the third MAM domainof TANGO 239 (SEQ ID NO: 2). The MAM consensus sequence is availablefrom the HMMer version 2.0 software as Accession Number PF00629.Software for HMM-based profiles is available fromhttp://www.csc.ucsc.edu/research/compbio/sam.html and fromhttp://genome.wustl.edu/eddy/hmmer.html. A MAM domain of TANGO 239extends, for example, from about amino acids 26 to 169, about aminoacids 170 to 329, about amino acids 342 to 498, and/or about amino acids509 to 666 of SEQ ID NO: 2.

[0173] Also included within the scope of the present invention are TANGO239 proteins having a signal sequence. In certain embodiments, a TANGO239 family member has the amino acid sequence of SEQ ID NO: 1, and thesignal sequence is located at amino acids 1 to 16, 1 to 17, 1 to 18, 1to 19, and 1 to 20. In such embodiments of the invention, the domainsand the mature protein resulting from cleavage of such signal peptidesare also included herein. For example, the cleavage of a signal sequenceconsisting of amino acids 1 to 18 of SEQ ID NO: 2 results in a matureTANGO 239 protein corresponding to amino acids 19 to 686 of SEQ ID NO:2. The signal sequence is normally cleaved during M; 15processing of themature protein.

[0174] Various features of human TANGO 239, form 1 and form 2, and mouseTANGO are summarized below.

[0175] Human TANGO 239 Form 1

[0176] A cDNA encoding human TANGO 239 was identified by screening anIL-1β stimulated astrocyte library. A clone, comprising human TANGO 239,was selected for complete sequencing based on its ability to direct thesecretion of a protein of approximately 60 kDa in 35S labeledsupernatants of 293T cells.

[0177] TANGO 239 includes a 3413 nucleotide cDNA (FIG. 1; SEQ ID NO: 1).In one embodiment, TANGO 239 is referred to as TANGO 239, form 1. Theopen reading frame of this TANGO 239, form 1 cDNA comprises nucleotides344 to 1990 of SEQ ID NO: 1, and encodes a secreted protein comprisingthe 550 amino acid depicted in FIG. 1 (SEQ ID NO: 2).

[0178] It is noted that the nucleotide sequence depicted in SEQ ID NO: 1contains Sal I and Not I adapter sequences on the 5′ and 3′ ends(GTCGACCCACGCGTCCC, nucleotides 1 to 16 of SEQ ID NO: 1 and GGGCGGCCGCof nucleotides 3404 to 3413 of SEQ ID NO: 1, respectively). Thus, it isto be understood that the nucleic acid molecules of the inventioninclude not only those sequences with such adaptor sequences but alsothe nucleic acid sequences described herein lacking the adaptorsequences.

[0179] The signal peptide prediction program SIGNALP (Nielsen et al.(1997) Protein Engineering 10:1-6) predicted that human TANGO 239, form1 includes an 18 amino acid signal peptide (amino acids 1 to about aminoacid 18 of SEQ ID NO: 2) preceding the mature TANGO 239, form 1 protein(corresponding to about amino acid 19 to amino acid 550 of SEQ ID NO:2). Human TANGO 239, form 1 is predicted to have a molecular weight ofapproximately 61.5 kDa prior to cleavage of its signal peptide and amolecular weight of approximately 59.5 kDa subsequent to cleavage of itssignal peptide.

[0180] Human TANGO 239, form 1 includes three MAM domains from aboutamino acids 24 to 169, amino acids 170 to 329, and amino acids 340 to496 of SEQ ID NO: 2.

[0181]FIG. 2 depicts a hydropathy plot of human TANGO 239, form 1, thedetails of which are described herein. As shown in the hydropathy plot,the hydrophobic region at the beginning of the plot which corresponds toabout amino acids 1 to 18 of SEQ ID NO: 2 is the signal sequence ofTANGO 239, form 1 (SEQ ID NO: 2).

[0182] A clone, EpDH233, which encodes human TANGO 239 form 1 wasdeposited as part of EpDHMixl with the American Type Culture Collection(ATCC, 10801 University Boulevard, Manassas, Va. 20110-2209) on Nov. 20,1998 which was assigned Accession Number 98999. This deposit will bemaintained under the terms of the Budapest Treaty on the InternationalRecognition of the Deposit of Microorganisms for the Purposes of patentProcedure. This deposit was made merely as a convenience to those ofskill in the art and is not an admission that a deposit is requiredunder 35 U.S.C. §112.

[0183] Human TANGO 239 Form 2

[0184] A cDNA encoding full length human TANGO 239 was identified byscreening an IL-1β stimulated astrocyte library. A clone comprisinghuman TANGO 239 was selected for complete sequencing based on itsability to direct the secretion of a protein of approximately 102.9 kDain ³⁵S labeled supernatants of 293 T cells.

[0185] Human TANGO 239 includes a 3413 nucleotide cDNA (FIG. 4; SEQ IDNO: 3). In one embodiment, human TANGO 239 is referred to as TANGO 239,form 2. The open reading frame of this TANGO 239, form 2 cDNA comprisesnucleotides 344 to 2395 (SEQ ID NO: 3), and encodes a secreted proteincomprising the 686 amino acid depicted in FIG. 4 (SEQ ID NO: 4). It isnoted that the nucleotide sequence depicted in SEQ ID NO: 3 contains SalI adaptor sequences and adapter sequences on the 5′ and 3′ ends,respectively.

[0186] The signal peptide prediction program SIGNALP (Nielsen et al.(1997) Protein Engineering 10:1-6) predicted that human TANGO 239, form2 includes an 18 amino acid signal peptide (amino acids 1 to about aminoacid 18 of SEQ ID NO: 4) preceding the mature TANGO 239, form 2 protein(corresponding to about amino acid 19 to amino acid 686 of SEQ ID NO:4). Human TANGO 239, form 2 is predicted to have a molecular weight ofapproximately 102.9 kDa prior to cleavage of its signal peptide and amolecular weight of approximately 100 kDa subsequent to cleavage of itssignal peptide.

[0187] Human TANGO 239, form 2 includes four MAM domains from aboutamino acids 26 to 169, amino acids 170 to 329, amino acids 340 to 496,and amino acids 509 to 666 of SEQ ID NO: 4.

[0188] Northern analysis of human TANGO 239 MRNA expression using TANGO239, form 2 nucleotide sequence as a probe revealed that TANGO 239 mRNAwas highly expressed in skeletal muscle, placenta, and peripheral bloodleukocytes. Expression was moderate in colon, thymus, kidney. Weakexpression was observed in the liver, small intestine, and lung. Noexpression was detected in the brain, heart and spleen.

[0189] Mouse TANGO 239

[0190] A mouse homologue of human TANGO 239 was identified. Mouse TANGO239 was identified by analyzing the sequences of clones present in amouse inflammation model cDNA library. This analysis led to theidentification of a clone, jymua038a02, encoding a mouse TANGO 239. Themouse TANGO 239 cDNA of this clone is 1029 nucleotides long (FIG. 5; SEQID NO: 5). It is noted that the nucleotide sequence depicted in SEQ IDNO: 5 contains Sal I and Not I adapter sequences on the 5′ and 3′ ends,respectively. The open reading frame of this cDNA, nucleotides 209 to370 of SEQ ID NO: 5, encodes a 54 amino acid secreted protein (FIG. 5;SEQ ID NO: 6).

[0191] In situ tissue screening was performed on mouse adult andembryonic tissue to analyze for the expression of mouse TANGO 239 MRNA.In summary, expression in the adult mouse appeared to be restricted tobone structures. The in situ screen only detected expression indeveloping bones of embryos starting at E14.5. Expression was weak butwas clearly detectable in the skull, scapula, sternum, vertebrae,incisor teeth, and femur. Adult tissues did not include bone orcartilage. Photoemulsion technique will be necessary to determinewhether expression is from osteoblasts, osteoclasts, or chondrocytes. Nosignal was detected in the following tissues: brain (included a sensecontrol), spinal cord, eye and harderian gland, submandibular gland,white fat, brown fat, stomach, heart (included a sense control), lung(included a sense control), liver (included a sense control), kidney(included a sense control), adrenal gland, colon, small intestine,thymus, lymph node, spleen, pancreas (included a sense control),skeletal muscle, bladder, testes, ovaries, placenta (included a sensecontrol). In the case of embryonic expression, the following resultswere obtained: at E13.5, no signal was observed. At E14.5, a weak signalwas observed outlining the vertebrae, incisors, and femur (included asense control). At E15.5, most developing bone structures appeared to beoutlined including the skull, Meckel's cartilage, scapula, vertebrae,primordium of basisphenoid bone, and femur (included a sense control).At E16.5 and E18.5, most developing bone structures had a weak signal ina pattern which outline the bone structures (included a sense control).At P1.5, a weak signal was associated with many developing bonestructures. The most noticeable structures included the skull,basisphenoid bone, vertebrae, Meckel's cartilage and/or incisor teeth ofthe upper and lower jaw, sternum, scapula, and femur (included a sensecontrol).

[0192] Human and mouse TANGO 239 sequences exhibit considerablesimilarity at the protein, nucleic acid, and open reading frame levels.An alignment (made using the ALIGN software {Myers and Miller (1989)CABIOS, ver. 2.0}; BLOSUM 62 scoring matrix; gap penalties-12/-4),reveals a protein identity of 79.6%. The human and mouse TANGO 239 fulllength cDNAs are 58.8% identical, as assessed using the same softwareand parameters as indicated (without the BLOSUM 62 scoring matrix). Inthe respective ORFs, calculated in the same fashion as the full lengthcDNAs, human and mouse TANGO 239 are 77.2% identical.

[0193] Uses of TANGO 239 Nucleic Acids, Polypeptides and ModulatorsThereof

[0194] As discussed above, the MAM domains of human TANGO 239 haveadhesion function. Thus, the human TANGO 239 proteins of the inventionlikely play a role in cellular adhesion and therefore, human TANGO 239proteins, nucleic acid molecules and/or modulators can be used tomodulate cellular adhesion.

[0195] As human TANGO 239 was originally identified in an astrocytelibrary, human TANGO 239 nucleic acids, proteins, and modulators thereofcan be used to modulate the proliferation, activation, development,differentiation, and/or function of glial cells e.g., astrocytes. HumanTANGO 239 nucleic acids, proteins and modulators thereof can be used totreat glial cell-related disorders, e.g., astrocytoma and glioblastoma

[0196] As TANGO 239 exhibits expression in the lung, TANGO 239polypeptides, nucleic acids, or modulators thereof, can be used to treatpulmonary (lung) disorders, such as atelectasis, pulmonary congestion oredema, chronic obstructive airway disease (e.g., emphysema, chronicbronchitis, bronchial asthma, and bronchiectasis), diffuse interstitialdiseases (e.g., sarcoidosis, pneumoconiosis, hypersensitivitypneumonitis, Goodpasture's syndrome, idiopathic pulmonary hemosiderosis,pulmonary alveolar proteinosis, desquamative interstitial pneumonitis,chronic interstitial pneumonia, fibrosing alveolitis, hamman-richsyndrome, pulmonary eosinophilia, diffuse interstitial fibrosis,Wegener's granulomatosis, lymphomatoid granulomatosis, and lipidpneumonia), or tumors (e.g., bronchogenic carcinoma, bronchiolovlveolarcarcinoma, bronchial carcinoid, hamartoma, and mesenchymal tumors).

[0197] As TANGO 239 exhibits expression in the small intestine, TANGO239 polypeptides, nucleic acids, or modulators thereof, can be used totreat intestinal disorders, such as ischemic bowel disease, infectiveenterocolitis, Crohn's disease, benign tumors, malignant tumors (e.g.,argentaffinomas, lymphomas, adenocarcinomas, and sarcomas),malabsorption syndromes (e.g., celiac disease, tropical sprue, Whipple'sdisease, and abetalipoproteinemia), obstructive lesions, hernias,intestinal adhesions, intussusception, or volvulus.

[0198] As TANGO 239 exhibits expression in the spleen, TANGO 239 nucleicacids, proteins, and modulators thereof can be used to modulate theproliferation, differentiation, and/or function of cells that form thespleen, e.g., cells of the splenic connective tissue, e.g., splenicsmooth muscle cells and/or endothelial cells of the splenic bloodvessels. TANGO 239 nucleic acids, proteins, and modulators thereof canalso be used to modulate the proliferation, differentiation, and/orfunction of cells that are processed, e.g., regenerated or phagocytizedwithin the spleen, e.g., erythrocytes and/or B and T lymphocytes andmacrophages. Thus TANGO 239 nucleic acids, proteins, and modulatorsthereof can be used to treat spleen, e.g., the fetal spleen, associateddiseases and disorders. Examples of splenic diseases and disordersinclude e.g., splenic lymphoma and/or splenomegaly, and/or phagocytoticdisorders, e.g., those inhibiting macrophage engulfment of bacteria andviruses in the bloodstream.

[0199] As TANGO 239 exhibits expression in the heart, TANGO 239 nucleicacids, proteins, and modulators thereof can be used to treat heartdisorders, e.g., ischemic heart disease, atherosclerosis, hypertension,angina pectoris, Hypertrophic Cardiomyopathy, and congenital heartdisease.

[0200] As TANGO 239 exhibits expression in bone structures, TANGO 239nucleic acids, proteins, and modulators thereof can be used to modulatethe proliferation, differentiation, and/or function of bone andcartilage cells, e.g., chondrocytes and osteoblasts, and to treat boneand/or cartilage associated diseases or disorders. Examples of boneand/or cartilage diseases and disorders include bone and/or cartilageinjury due to for example, trauma (e.g., bone breakage, cartilagetearing), degeneration (e.g., osteoporosis), degeneration of joints,e.g., arthritis, e.g., osteoarthritis, and bone wearing.

[0201] Other TANGO 239 activities include at least one or more of thefollowing activities: 1) modulation of cellular adhesion, either invitro or in vivo; 2) regulation of cell trafficking and/or migration; 3)modulation of cellular proliferation; 4) modulation of inflammation;and/or 5) modulation of a signaling pathway. Thus, TANGO 239 proteins,nucleic acids and/or modulators can be used to treat a disordercharacterized by aberrant TANGO 239 expression and/or an aberrant TANGO239 activity.

[0202] Human TANGO 219

[0203] A CDNA encoding human TANGO 219 was identified by analyzing thesequences of clones present in a prostate stroma CDNA library. Thisanalysis led to the identification of a clone, jthqc101c05, encodinghuman TANGO 219. The human TANGO 219 cDNA of this clone is 1268nucleotides long (FIG. 6; SEQ ID NO: 7). The open reading frame of thisCDNA, nucleotides 106 to 552 of SEQ ID NO: 7, encodes a 149 amino acidsecreted protein (FIG. 6; SEQ ID NO: 8).

[0204] In one embodiment of a nucleotide sequence of human TANGO 219,the nucleotide at position 186 is an guanine (G). In this embodiment,the amino acid at position 27 is glutamate (E). In another embodiment ofa nucleotide sequence of human TANGO 219, the nucleotide at position 186is a cytosine (C). In this embodiment, the amino acid at position 27 isaspartate (D). In another embodiment of a nucleotide sequence of humanTANGO 219, the nucleotide at position 261 is guanine (G). In thisembodiment, the amino acid at position 52 is glutamate (E). In anotherembodiment of a nucleotide sequence of human TANGO 219, the nucleotideat position 261 is cytosine (C). In this embodiment, the amino acid atposition 52 is aspartate (D). In another embodiment of a nucleotidesequence of human TANGO 219, the nucleotide at position 309 is adenine(A). In this embodiment, the amino acid at position 68 is glutamate (E).In another embodiment of a nucleotide sequence of human TANGO 219, thenucleotide at position 309 is cytosine (C). In this embodiment, theamino acid at position 68 is aspartate (D).

[0205] The signal peptide prediction program SIGNALP (Nielsen et al.(1997) Protein Engineering 10:1-6) predicted that human TANGO 219includes an 18 amino acid signal peptide (amino acid 1 to about aminoacid 18 of SEQ ID NO: 8) preceding the mature TANGO 219 proteincorresponding to about amino acid 19 to amino acid 149 of SEQ ID NO: 8.The TANGO 219 protein molecular weight is 17.0 kDa prior to the cleavageof the signal peptide, 14.8 kDa after cleavage of the signal peptide.

[0206] Northern analysis of TANGO 219 in human tissues revealed that anapproximately 1.25 kB transcript is weakly expressed in the heart andnot in other tissues tested such as, for example, brain, placenta, lung,liver, skeletal muscle, kidney, pancreas, stomach, thyroid, spinal cord,lymph node, adrenal gland, trachea, bone marrow, spleen, thymus,prostate, testes, ovary, small intestine, colon, and peripheral bloodleukocytes.

[0207] The human gene for TANGO 219 was mapped on radiation hybridpanels to the long arm of chromosome 5, in the region q21-22. Flankingmarkers for this region are NIB916 and D5S492. The MANA2 (mannosidase,type2), APC (adenomatous polyposis coli), PST (polysialytransferase),CAST (calpastatin) genes also map to this region of the humanchromosome. The LGMD1A (limb girdle muscular dystrophy) loci also mapsto this region of the human chromosome. This region is syntenic to mousechromosomes 11 and 18. The Q (quinky), pdw (proportional dwarf), andly11 (lymphoblastomic leukemia) loci also map to this region of themouse chromosome. The Chr.11-fer (protein kinase, testis specific)Chr.18-mcc (mutated in colorectal cancers), pk (plucked), donl(divergent of neuregulin 1) genes also map to this region of the mousechromosome.

[0208] Clone EpT219, which encodes human TANGO 219, was deposited withthe American Type Culture Collection (10801 University Boulevard,Manassas, Va. 20110-2209) on Sep. 25, 1998 and assigned Accession Number98899. This deposit will be maintained under the terms of the BudapestTreaty on the International Recognition of the Deposit of Microorganismsfor the Purposes of patent Procedure. This deposit was made merely as aconvenience for those of skill in the art and is not an admission that adeposit is required under 35 U.S.C. §112.

[0209]FIG. 7 depicts a hydropathy plot of human TANGO 219, the detailsof which are described herein.

[0210] Mouse TANGO 219

[0211] A mouse homolog of human TANGO 219 was identified. A cDNAencoding mouse TANGO 219 was identified by analyzing the sequences ofclones present in a mouse cDNA library. This analysis led to theidentification of a clone encoding mouse TANGO 219. The mouse TANGO 219cDNA of this clone is 397 nucleotides long (FIG. 8; SEQ ID NO: 9). Theopen reading frame of this cDNA, comprises nucleotides 2 to 370 of SEQID NO: 9, and encodes a secreted protein comprising the 123 amino acidsequence depicted in FIG. 8 (SEQ ID NO: 10).

[0212] In one embodiment of a nucleotide sequence of mouse TANGO 219,the nucleotide at position 127 is an guanine (G). In this embodiment,the amino acid at position 42 is glutamate (E). In another embodiment ofa nucleotide sequence of mouse TANGO 219, the nucleotide at position 127is a cytosine (C). In this embodiment, the amino acid at position 42 isaspartate (D). In another embodiment of a nucleotide sequence of mouseTANGO 219, the nucleotide at position 154 is guanine (G). In thisembodiment, the amino acid at position 51 is glutamate (E). In anotherembodiment of a nucleotide sequence of mouse TANGO 219, the nucleotideat position 154 is cytosine (C). In this embodiment, the amino acid atposition 51 is aspartate (D). In another embodiment of a nucleotidesequence of mouse TANGO 219, the nucleotide at position 226 is adenine(A). In this embodiment, the amino acid at position 75 is glutamate (E).In another embodiment of a nucleotide sequence of mouse TANGO 219, thenucleotide at position 226 is cytosine (C). In this embodiment, theamino acid at position 75 is aspartate (D).

[0213] The signal peptide prediction program SIGNALP (Nielsen et al.(1997) Protein Engineering 10:1-6) predicted that mouse TANGO 219includes a 40 amino acid signal peptide (amino acid 1 to about aminoacid 40 of SEQ ID NO: 10) preceding the mature mouse TANGO 219 protein(corresponding to about amino acid 41 to amino acid 123 of SEQ ID NO:10). The TANGO 219 protein molecular weight is 17.0 kDa prior to thecleavage of the signal peptide, 14.8 kDa after cleavage of the signalpeptide.

[0214] Uses of TANGO 219 Nucleic Acids Polypeptides and ModulatorsThereof

[0215] As TANGO 219 was originally found in a prostate stroma library,TANGO 219 nucleic acids, proteins, and modulators thereof can be used tomodulate the proliferation, differentiation, and/or function, e.g.,secretory activity, of the prostate cells. Such molecules can also beuseful for treatment of prostate diseases or disorders, e.g., acute orchronic prostatitis (and the resulting urinary tract infection), benignnodular enlargement, and prostatic carcinoma.

[0216] As TANGO 219 appears to be preferentially expressed in the heartand not in many other tissues, TANGO 219 nucleic acids, proteins, andmodulators thereof can be used to modulate the proliferation,differentiation, and/or function of cardiac cells. Thus TANGO 219 playsa role in regulating cardiac function, including modulating cardiacrhythm and strength of contraction, and the heart's response to stress.Such molecules can also be useful for treatment of heart diseases orconditions, e.g., ischemic heart disease or atherosclerosis, orcerebrovascular accidents, or more particularly, treating or preventingconditions involving heart contraction, and the impulse generating nodesand cardiac muscle cells, e.g., ventricular fibrillation or myocardialinfarction.

[0217] TANGO 232

[0218] A TANGO 232 family member includes a signal sequence. In certainembodiments, a TANGO 232 family member has the amino acid sequence ofSEQ ID NO: 14, and the signal sequence is located at amino acids 1 to20, 1 to 21, 1 to 22, 1 to 23, or 1 to 24. In such embodiments of theinvention, the domains and the mature protein resulting from cleavage ofsuch signal peptides are also included herein. For example, the cleavageof a signal sequence consisting of amino acids 1-22 of SEQ ID NO: 14,results in a mature TANGO 232 protein corresponding to amino acids 23 to238 of SEQ ID NO: 14. The signal sequence is normally cleaved duringprocessing of the mature protein.

[0219] In another example, a TANGO 232 family member also includes oneor more of the following domains: (1) an extracellular domain; (2) atransmembrane domain; and (3) a cytoplasmic domain.

[0220] In one embodiment, a TANGO 232 protein contains an extracellulardomain of about amino acids 23-194 of SEQ ID NO: 14. In anotherembodiment, a TANGO 232 protein contains a transmembrane domain of aboutamino acids 195-216 of SEQ ID NO: 14. In another embodiment, a TANGO 232protein contains a cytoplasmic domain of about amino acids 217-238 ofSEQ ID NO: 14.

[0221] TANGO 232 family members can also include a cysteine-rich domain.As used herein, a “cysteine-rich domain” includes at least about 30 to70 amino acid residues, more preferably at least about 40 to 60 aminoacid residues, and most preferably at least about 40 to 50 amino acidresidues. Of these residues at least about five are cysteine residues.The cysteine-rich domain can also include at least the followingconsensus sequence:C-D-Y-D-Xaa(1)-C-R-H-L-Q-V-Xaa(2)-C-Xaa(3)-E-L-Q-Xaa(1)-Xaa(4)-Xaa(5)-P-Xaa(4)-Xaa(4)-C-L-C-P-G-L-S-Xaa(6)-Xaa(7)-Xaa(7)-Q-Xaa(2)-P-Xaa(8)-Xaa(2)-P-R-Xaa(4)-G(SEQ ID NO:); wherein Xaa(1) is an amino acid with a basic side chain,e.g., R, H, or K; Xaa(2) is an amino acid with an uncharged polar sidechain or a nonpolar side chain, e.g., S, P, or Q; Xaa(3) is an aminoacid with a basic side chain or an uncharged polar side chain, e.g., Qor K; Xaa(4) is an amino acid with a nonpolar side chain, e.g., A, P, V,L or M; Xaa(5) is an amino acid with an acidic side chain or anuncharged polar side chain, e.g., G or E; Xaa(6) is an amino acid with abasic side chain or an uncharged polar side chain, e.g., S or R; Xaa(7)is an amino acid with an acidic side chain or a nonpolar side chain,e.g., P, E, A, or D; Xaa(8) is an amino acid with an acidic side chain,e.g., D or E.

[0222] The cysteine-rich domain of macaque TANGO 232 is located fromamino acid residues 49 to 90 of SEQ ID NO: 14, and the cysteine residuesare at positions 49, 54, 61, 72, and 74.

[0223] In a preferred embodiment, a TANGO 232 polypeptide is a humanpolypeptide which includes a cysteine-rich domain as described herein.Preferably the human polypeptide is at least about 95%, 96%, 97%, or 98%identical to the macaque TANGO 232 amino acid sequence shown in SEQ IDNO: 14.

[0224] Macaque TANGO 232

[0225] A cDNA encoding macaque TANGO 232 was identified by analyzing thesequences of clones present in a macaque adipose tissue cDNA library.

[0226] This analysis led to the identification of a clone, Atkfa110e6,encoding macaque TANGO 232. The cDNA of this clone is 1937 nucleotideslong (FIG. 9; SEQ ID NO: 11). It is noted that the nucleotide sequencedepicted in SEQ ID NO: 11 contains Sal I and Not I adapter sequences onthe 5′ and 3′ ends, respectively.

[0227] The open reading frame of this cDNA, nucleotides 96 to 809 of SEQID NO: 12, encodes a 238 amino acid transmembrane protein (FIG. 9; SEQID NO: 12).

[0228] In one embodiment of a nucleotide sequence of macaque TANGO 232,the nucleotide at position 182 is an adenine (A). In this embodiment,the amino acid at position 29 is glutamate (E). In another embodiment ofa nucleotide sequence of macaque TANGO 232, the nucleotide at position182 is a cytosine (C). In this embodiment, the amino acid at position 29is aspartate (D). In another embodiment of a nucleotide sequence ofmacaque TANGO 232, the nucleotide at position 185 is adenine (A). Inthis embodiment, the amino acid at position 30 is glutamate (E). Inanother embodiment of a nucleotide sequence of macaque TANGO 232, thenucleotide at position 185 is cytosine (C). In this embodiment, theamino acid at position 30 is aspartate (D). In another embodiment of anucleotide sequence of macaque TANGO 232, the nucleotide at position 188is guanine (G). In this embodiment, the amino acid at position 31 isglutamate (E). In another embodiment of a nucleotide sequence of macaqueTANGO 232, the nucleotide at position 188 is cytosine (C). In thisembodiment, the amino acid at position 31 is aspartate (D).

[0229] The signal peptide prediction program SIGNALP (Nielsen et al.(1997) Protein Engineering 10:1-6) predicted that macaque TANGO 232includes an 22 amino acid signal peptide (amino acid 1 to about aminoacid 22 of SEQ ID NO: 12) preceding the mature macaque TANGO 232 protein(corresponding to about amino acid 23 to amino acid 238 of SEQ ID NO:12).

[0230] There are eight conserved cysteines in the extracellular domainat positions 48, 53, 60, 70, 73, 105, 152 and 183 of SEQ ID NO: 12.Macaque TANGO 232 has a high proportion of charged amino acids in thepredicted extracellular (22%, not including histidine) and cytoplasmic(27%) domains. Macaque TANGO 232 is predicted to have a molecular weightof 25.4 kDa prior to cleavage of its signal peptide and a molecularweight of 23.0 kDa subsequent to cleavage of its signal peptide.

[0231] A clone, EpT232m, which encodes macaque TANGO 232, was depositedwith the American Type Culture Collection (10801 University Boulevard,Manassas, Va. 20110-2209) on Jan. 7, 1999 and assigned Accession Number207045. This deposit will be maintained under the terms of the BudapestTreaty on the International Recognition of the Deposit of Microorganismsfor the Purposes of patent Procedure. This deposit was made merely as aconvenience for those of skill in the art and is not an admission that adeposit is required under 35 U.S.C. §112.

[0232]FIG. 10 depicts a hydropathy plot of macaque TANGO 232, thedetails of which are described herein. The dashed vertical lineseparates the signal sequence (amino acids 1-22 of SEQ ID NO: 12) on theleft from the mature protein (amino acids 23-238 of SEQ ID NO: 12) onthe right.

[0233] In one embodiment, macaque TANGO 232 is predicted to be atransmembrane protein having a 172 amino acid extracellular domain(amino acids 23-194 of SEQ ID NO: 12), a 22 amino acid transmembranedomain (amino acids 195-216 of SEQ ID NO: 12), and a 22 amino acidcytoplasmic domain (amino acids 217-238 of SEQ ID NO: 12).Alternatively, in another embodiment, a macaque TANGO 232 proteincontains an extracellular domain at amino acid residues 217 to 238, atransmembrane domain at amino acid residues 195 to 216, and acytoplasmic domain at amino acid residues 1 to 194 of SEQ ID NO: 12.

[0234] An N-glycosylation site NATV is found from amino acids 132 to135. A protein kinase C phosphorylation site TVR is found from aminoacids 134 to 136. An N-myristoylation site GSEAAQ is found from aminoacids 121 to 126. A second N-myristoylation site GLKPGG is found fromamino acids 142 to 147. A third N-myristoylation site GLEGAD is foundfrom amino acids 171 to 176. A fourth N-myristoylation site GVGTAL isfound from amino acids 201 to 206.

[0235]FIG. 11 depicts an alignment of a portion of the macaque TANGO 232amino acid sequence (amino acids 1-132 of SEQ ID NO: 12) with atranslation of a rabbit nucleotide sequence (GenBank Accession NumberC83084; SEQ ID NO: 45) and a mouse nucleotide sequence (clone jtmoa31f1;SEQ ID NO: 18). This alignment defines a cysteine-rich domain that isconserved and which is described in detail herein. The arrows indicatethe conserved cysteine residues at positions 49, 54, 61, 72, and 74. Anadditional cysteine residue at position 106 is conserved in the macaqueand rabbit sequences.

[0236] Human TANGO 232

[0237] A clone, Athke96c4, encoding human TANGO 232 was identified. ThecDNA of this clone is 1459 nucleotides long (FIG. 12; SEQ ID NO: 13). Itis noted that the nucleotide sequence depicted in SEQ ID NO: 13 containsa Not I adapter sequence on the 3′ end, respectively. In one embodiment,human TANGO 232 is referred to as human TANGO 232, form 1. The openreading frame of this human TANGO 232, form 1 cDNA comprises nucleotides1 to 366 of SEQ ID NO: 13, and encodes a polypeptide comprising the 122amino acid sequence shown in FIG. 12 (SEQ ID NO: 14).

[0238] Secretion assays indicate that the polypeptide encoded by humanTANGO 232 is not secreted and thus, likely a transmembrane protein. Thesecretion assays were performed essentially as follows: 8×10⁵ 293T cellswere plated per well in a 6-well plate and the cells were incubated ingrowth medium (DMEM, 10% fetal bovine serum, penicillin/ strepomycin) at37° C., 5% CO₂ overnight. 293T cells were transfected with 2 μg offull-length TANGO 232 inserted in the pMET7 vector/well and 10 μgLipofectAMINE (GIBCO/BRL Cat. #18324-012) /well according to theprotocol for GIBCO/BRL LipofectAMINE. The transfectant was removed 5hours later and fresh growth medium was added to allow the cells torecover overnight. The medium was removed and each well was gentlywashed twice with DMEM without methionine and cysteine (ICN Cat.#16-424-54). 1 ml DMEM without methionine and cysteine with 50 μCiTrans-³⁵S (ICN Cat. #51006) was added to each well and the cells wereincubated at 37° C., 5% CO₂ for the appropriate time period. A 150 μlaliquot of conditioned medium was obtained and 150 μl of 2×SDS samplebuffer was added to the aliquot. The sample was heat-inactivated andloaded on a 4-20% SDS-PAGE gel. The gel was fixed and the presence ofsecreted protein was detected by autoradiography.

[0239] The signal peptide prediction program SIGNALP (Nielsen et al.(1997) Protein Engineering 10:1-6) predicted that human TANGO 232 form 1does not appear to include a signal peptide. Accordingly, the maturehuman TANGO 232 form 1 protein corresponds to about amino acid 1 toabout amino acid 122 of SEQ ID NO: 14.

[0240] In one embodiment, human TANGO 232 form 1 protein is atransmembrane protein that contains an extracellular domain at aminoacid residues 1 to 78, a transmembrane domain at amino acid residues 79to 100, and a cytoplasmic domain at amino acid residues 101 to 122 ofSEQ ID NO: 14. Alternatively, in another embodiment, a human TANGO 232form 1 protein contains an extracellular domain at amino acid residues101 to 122, a transmembrane domain at amino acid residues 79 to 100, anda cytoplasmic domain at amino acid residues 1 to 78 of SEQ ID NO: 14.

[0241] A clone, EpT232h, which encodes human TANGO 232, was depositedwith the American Type Culture Collection (10801 University Boulevard,Manassas, Va. 20110-2209) on Jan. 7, 1999 and assigned Accession Number207046. This deposit will be maintained under the terms of the BudapestTreaty on the International Recognition of the Deposit of Microorganismsfor the Purposes of patent Procedure. This deposit was made merely as aconvenience for those of skill in the art and is not an admission that adeposit is required under 35 U.S.C. §112.

[0242]FIG. 13 depicts an alignment of a portion of the cDNA sequence ofmacaque TANGO 232 (nucleotides 424 to 1937 of SEQ ID NO: 11) andnucleotides 1 to 1459 of human TANGO 232 clone Athke96c4 (SEQ ID NO:13). An evaluation of the sequence similarity using the program FASTA(Pearson, W. R., and Lipman, D. J. (1988) Proc. Natl Acad. Sci. USA85:2444-2448) version 2.0u53 (Jul. 1996) indicates that there is 83.4%identity between the two sequences.

[0243]FIG. 14 depicts an alignment of a portion of the amino acidsequence of macaque TANGO 232 (amino acids 93 to 238 of SEQ ID NO: 12)and human TANGO 232 clone Athke96c4 (SEQ ID NO: 14). An evaluation ofthe sequence similarity using the program FASTA (Pearson, W. R., andLipman, D. J. (1988) Proc. Natl Acad. Sci. USA 85:2444-2448) version2.0u53 (July 1996) indicates that there is 94.9% identity between thetwo sequences.

[0244] Another cDNA clone, Arhoc109b10, encoding human TANGO 232 wasidentified. The cDNA of this clone is 1136 nucleotides long (FIG. 15;SEQ ID NO: 15). It is noted that the nucleotide sequence depicted in SEQID NO: contains Sal I and Not I adapter sequences on the 5′ and 3′ ends,respectively.

[0245] In one embodiment, human TANGO 232 is referred to as human TANGO232, form 2. The open reading frame of this human TANGO 232, form 2cDNA, nucleotides 110 to 823 of SEQ ID NO: 15, encodes a 238 amino acidtransmembrane protein shown in FIG. 15 (SEQ ID NO: 16).

[0246] In one embodiment of a nucleotide sequence of human TANGO 232form 2, the nucleotide at position 196 is an adenine (A). In thisembodiment, the amino acid at position 30 is glutamate (E). In anotherembodiment of a nucleotide sequence of human TANGO 232 form 2, thenucleotide at position 196 is a cytosine (C). In this embodiment, theamino acid at position 30 is aspartate (D). In another embodiment of anucleotide sequence of human TANGO 232 form 2, the nucleotide atposition 199 is adenine (A). In this embodiment, the amino acid atposition 31 is glutamate (E). In another embodiment of a nucleotidesequence of human TANGO 232 form 2, the nucleotide at position 199 iscytosine (C). In this embodiment, the amino acid at position 31 isaspartate (D). In another embodiment of a nucleotide sequence of humanTANGO 232 form 2, the nucleotide at position 202 is guanine (G). In thisembodiment, the amino acid at position 32 is glutamate (E). In anotherembodiment of a nucleotide sequence of human TANGO 232 form 2, thenucleotide at position 202 is cytosine (C). In this embodiment, theamino acid at position 32 is aspartate (D).

[0247] The signal peptide prediction program SIGNALP (Nielsen et al.(1997) Protein Engineering 10:1-6) predicted that human TANGO 232 form 2includes a 22 amino acid signal peptide (amino acid 1 to about aminoacid 22 of SEQ ID NO: 16) preceding the mature human TANGO 232 form 2protein (corresponding to about amino acid 23 to amino acid 238 of SEQID NO: 16).

[0248] In one embodiment, human TANGO 232 form 2 protein is atransmembrane protein that contains an extracellular domain at aminoacid residues 23 to 194, a transmembrane domain at amino acid residues195 to 216, and a cytoplasmic domain at amino acid residues 217 to 238of SEQ ID NO: 16. Alternatively, in another embodiment, a human TANGO232 form 2 protein contains an extracellular domain at amino acidresidues 217 to 238, a transmembrane domain at amino acid residues 195to 216, and a cytoplasmic domain at amino acid residues 1 to 194 of SEQID NO: 16.

[0249] The human gene for TANGO 232 was mapped on radiation hybridpanels to the long arm of chromosome 11, in the region q13. Flankingmarkers for this region are D11S1965 and WI-1409. The ARRB1 (arrestin,beta), GIF (gastric intrinsic factor), ACTN3 (actinin, alpha 3) genesalso map to this region of the human chromosome. The HBM (high bonemass), OPTB1 (osteoporosis, auto.rec.), OPPG (osteoporosis, pseudogliomasyndrome), BBS1 (Bardet-Biedl syndrome), HND (Hartnup disorder), MKS2(Meckel syndrome 2). This region is syntenic to mouse chromosome 7. Theoc (osteosclerotic), dc (dancer), nmd (meuromuscular degeneration), ocd(osteochondrodystrophy) loci also map to this region of the mousechromosome. The pcx (pyruvate decarboxylase), chk (choline kinase), galn(galanin) genes also map to this region of the mouse chromosome.

[0250] Mouse TANGO 232

[0251] A cDNA encoding mouse TANGO 232 was identified by analyzing thesequences of clones present in a mouse osteoblast, LPS stimulated cDNAlibrary. This analysis led to the identification of a clone,jtmoa3lfl,encoding mouse TANGO 232. The mouse TANGO 232 cDNA of thisclone is 2221 nucleotides long (FIG. 16; SEQ ID NO: 17). It is notedthat the nucleotide sequence depicted in SEQ ID NO: 17 contains a Sal Iadapter sequence on the 5′ end. The open reading frame of this cDNA,nucleotides 79 to 795 of SEQ ID NO: 17, encodes the 239 amino acidtransmembrane protein depicted in FIG. 16 (SEQ ID NO: 18).

[0252] In one embodiment of a nucleotide sequence of mouse TANGO 232,the nucleotide at position 171 is an adenine (A). In this embodiment,the amino acid at position 31 is glutamate (E). In another embodiment ofa nucleotide sequence of mouse TANGO 232, the nucleotide at position 171is a cytosine (C). In this embodiment, the amino acid at position 31 isaspartate (D). In another embodiment of a nucleotide sequence of mouseTANGO 232, the nucleotide at position 177 is adenine (A). In thisembodiment, the amino acid at position 33 is glutamate (E). In anotherembodiment of a nucleotide sequence of mouse TANGO 232, the nucleotideat position 177 is cytosine (C). In this embodiment, the amino acid atposition 33 is aspartate (D). In another embodiment of a nucleotidesequence of mouse TANGO 232, the nucleotide at position 180 is guanine(G). In this embodiment, the amino acid at position 34 is glutamate (E).In another embodiment of a nucleotide sequence of mouse TANGO 232, thenucleotide at position 180 is cytosine (C). In this embodiment, theamino acid at position 34 is aspartate (D).

[0253] The signal peptide prediction program SIGNALP (Nielsen et al.(1997) Protein Engineering 10:1-6) predicted that mouse TANGO 232includes a 19 amino acid signal peptide (amino acid 1 to about aminoacid 19 of SEQ ID NO: 18) preceding the mature mouse TANGO 232 protein(corresponding to about amino acid 20 to amino acid 239 of SEQ ID NO:18).

[0254] In one embodiment, mouse TANGO 232 protein is a transmembraneprotein that contains an extracellular domain at amino acid residues 20to 192, a transmembrane domain at amino acid residues 193 to 216, and acytoplasmic domain at amino acid residues 217 to 239 of SEQ ID NO: 18.Alternatively, in another embodiment, a mouse TANGO 232 protein containsan extracellular domain at amino acid residues 217 to 239 of SEQ ID NO:18, a transmembrane domain at amino acid residues 193 to 216 of SEQ IDNO: 18, and a cytoplasmic domain at amino acid residues 1 to 192 of SEQID NO: 18.

[0255] In situ tissue screening was performed on mouse adult andembryonic tissue to analyze for the expression of mouse TANGO 232 mRNA.In summary, the embryonic signal pattern was suggestive of expression bydeveloping muscle. Expression was observed in a layer just under theskin beginning at E14.5. At later ages expression was also observedoutlining the ribs, skull, ear, and clavicle suggesting expression by oraround some bone structures. Expression was also detected from themesothelial cells outlining the pleural cavity. At E18.5, expression inthe smooth muscle of the small intestine was also detected but was notobserved at P1.5. Adult expression was observed in the skeletal andsmooth muscle in a weak or moderate multifocal pattern. Expression wasalso observed in the muscle layer of the bladder and in the labyrinthregion of the placenta. In particular, with respect to adult expression,the following results were obtained: A multifocal signal was observed inthe skeletal and smooth muscle (diaphragm). In addition, a strongersignal was observed along the edge of the diaphragm. This signal may befrom the peritoneum. A weak, multifocal signal which is predominately inthe muscle portion of the bladder tissue. A signal is observed in thelabyrinth zone of the placenta. No expression was observed in thefollowing tissues: Brain, spinal cord, eye and harderian gland,submandibular gland, white fat, brown fat, stomach, heart, lung, liver,kidney, adrenal gland, colon, small intestine, thymus, lymph node,spleen, pancreas, testes, and the ovaries.

[0256] With respect to embryonic expression, at E13.5, no positivesignal was detected. At E14.5, a weak signal was detected just under theskin along the back, stomach, and skull in a pattern suggestive of themuscle layer. Weak signal was also seen outlining the ribs. At E15.5, asignal was observed just under the skin along the back, leg, stomach,and chest. Signal was also seen outlining the ribs and along the skulland in the region of the ear. At E16.5, the signal was observed in themuscle layer just under the skin throughout the embryo. Signal was alsoseen outlining the ribs, regions of the skull, and muscles of the leg.The mesothelial cells lining the pleural cavity were also detected. Thediaphragm did not appear to be positive. At E18.5, the signal patternwas very similar to that observed at E16.5 with most of the thin musclelayers being positive thus outlining many major structures. In addition,the small intestine was outlined indicating some smooth muscleexpression. At P1.5, a signal in the region of the gut, heart, and headappears to have decreased. A moderate signal was still observed justunder the skin.

[0257] Human and mouse TANGO 232 sequences exhibit considerablesimilarity at the protein, nucleic acid, and open reading frame levels.An alignment (made using the ALIGN software {Myers and Miller (1989)CABIOS, ver. 2.0}; BLOSUM 62 scoring matrix; gap penaltiesn-12/-4),reveals a protein identity of 68.8%. The human and mouse TANGO 232 fulllength cDNAs are 69.1% identical, as assessed using the same softwareand parameters as indicated (without the BLOSUM 62 scoring matrix). Inthe respective ORFs, calculated in the same fashion as the full lengthcDNAs, human and mouse TANGO 232 are 72.6% identical.

[0258] Uses of TANGO 232 Nucleic Acids, Polypeptides, and ModulatorsThereof

[0259] Because TANGO 232 is expressed in subcutaneous adipose tissue,TANGO 232 polypeptides, nucleic acids, and modulators of TANGO 232expression or activity can be useful for modulation of adipocytefunction, e.g., fat metabolism. Such molecules can also be used to treatdisorders associated with abnormal fat metabolism, e.g., obesity,arteriosclerosis, or cachexia.

[0260] As mouse TANGO 232 was originally found in an LPS stimulatedmouse primary osteoblast library, TANGO 232 nucleic acids, proteins, andmodulators thereof can be used to modulate the proliferation,differentiation, and/or function of cells that form bone matrix, e.g.,osteoblasts and osteoclasts, and can be used to modulate the formationof bone matrix. Thus, TANGO 232 nucleic acids, proteins, and modulatorsthereof can be used to treat cartilage and bone associated diseases anddisorders, and can play a role in bone growth, formation, andremodeling. Examples of cartilage and bone associated diseases anddisorders include e.g., bone cancer, achondroplasia, myeloma, fibrousdysplasia, scoliosis, osteoarthritis, osteosarcoma, and osteoporosis.

[0261] TANGO 232 exhibits weak homology to the F3 domain of Ephrinreceptor and G-CSF receptor. G-CSF is the major growth factor involvedin the production of neutrophilic granulocytes. G-CSF exerts itsfunction via the activation of a membrane receptor that belongs to thesuper-family of hematopoietic receptors, also referred to as class Icytokine receptors. Thus, TANGO 232 polypeptides, nucleic acids, andmodulators of TANGO 232 expression or activity can be useful formodulation of the function of the G-CSF receptor in normalgranulopoiesis. TANGO 232 polypeptides, nucleic acids, and modulators ofTANGO 232 expression or activity can be useful for modulation ofG-CSF-induced STAT3 activation during basal granulopoiesis (low G-CSF)and “emergency” granulopoiesis (high G-CSF). Thus, TANGO 232polypeptides, nucleic acids, and modulators of TANGO 232 expression oractivity can be useful for the modulation of diseases characterized bydisturbed myeloid maturation such as severe congenital neutropenia andacute myeloblastic leukemia. In addition, the TANGO 232 proteins,nucleic acids and/or modulators can be used for the treatment of adisorder characterized by aberrant TANGO 232 expression and/or anaberrant TANGO 232 activity, such as maturation signaling.

[0262] TANGO 281

[0263] The TANGO 281 proteins and nucleic acid molecules comprisefamilies of molecules having certain conserved structural and functionalfeatures. In one example, a TANGO 281 family member consists of one ormore of the following domains: (1) an extracellular domain; (2) atransmembrane domain; and (3) a cytoplasmic domain.

[0264] In another embodiment, a TANGO 281 protein contains anextracellular domain at amino acids 1 to about 123 or a matureextracellular domain at about amino acid residues 39 to 123, atransmembrane domain at about amino acid residues 124 to 148, and acytoplasmic domain at about amino acid residues 149 to 245 of SEQ ID NO:20.

[0265] In another embodiment, a mature TANGO 281 protein contains aboutamino acid residues 39 to 245 of SEQ ID NO: 20. In another embodiment, aTANGO 281 family contains an extracellular domain at amino acids 1 toabout 112 or a mature extracellular domain at about amino acid residues27 to 112, a transmembrane domain at about amino acid residues 113 to137, and a cytoplasmic domain at about amino acid residues 138 to 213 ofSEQ ID NO: 20. In yet another embodiment, a mature TANGO 281 proteincontains about amino acid residues 27 to 213 of SEQ ID NO: 20.

[0266] In one embodiment, a TANGO 281 family member includes a signalsequence. In a preferred embodiment, a TANGO 281 family member has theamino acid sequence of SEQ ID NO: 20, and the signal sequence is locatedat about amino acids 1 to 38. In an another preferred embodiment, aTANGO 281 family member has the amino acid sequence of SEQ ID NO: 20,and the signal sequence is located at about amino acids 1 to 26.

[0267] A photosystem II 10kd phosphoprotein (PSBH) domain has beenidentified in the TANGO 281 proteins. The domain is also present in thechloroplast gene PSBH that encodes a 9-10 kDa thylakoid membrane protein(PSII-H) which is associated with photosystem II. In one embodiment, aTANGO 281 family member includes one or more PSBH domains having anamino acid sequence that is at least about 55%, preferably at leastabout 65%, more preferably at least 75%, yet more preferably at leastabout 85%, and most preferably at least about 95% identical to aminoacids 41 to 90 and/or amino acids 127 to 182 of SEQ ID NO: 20, which arethe PSBH domains of human TANGO 281.

[0268] In another embodiment, a TANGO 281 family member includes one ormore PSBH domains having an amino acid sequence that is at least about55%, preferably at least about 65%, more preferably at least about 75%,yet more preferably at least about 85%, and most preferably at leastabout 95% identical to amino acids 41 to 90 and/or amino acids 127 to182 of SEQ ID NO: 20, which are the PSBH domains of human TANGO 281includes one or more PSBH domain consensus sequences described herein,and has at least one TANGO 281 biological activity as described herein.

[0269] In another embodiment, a TANGO 281 family member includes one ormore PSBH domains having an amino acid sequence that is at least about55%, preferably at least about 65%, more preferably at least 75%, yetmore preferably at least about 85%, and most preferably at least about95% to 98% identical to amino acids 42 to 91 and/or amino acids 128 to183 of SEQ ID NO: 22, which are the PSBH domains of mouse TANGO 281.

[0270] In another embodiment, a TANGO 281 family member includes one ormore PSBH domains having an amino acid sequence that is at least about55%, preferably at least about 65%, more preferably at least about 75%,yet more preferably at least about 85%, and most preferably at leastabout 95% identical to amino acids 42 to 91 and/or amino acids 128 to183 of SEQ ID NO: 22, which are the PSBH domains of mouse TANGO 281,includes one or more PSBH domain consensus sequences described herein,and has at least one TANGO 281 biological activity as described herein.

[0271] Human TANGO 281

[0272] A cDNA encoding human TANGO 281 was identified by analyzing thesequences of clones present in a human megakarocyte cDNA library. Thisanalysis led to the identification of a clone, AThPb81d10, encodinghuman TANGO 281. The human TANGO 281 cDNA of this clone is 1812nucleotides long (FIG. 17; SEQ ID NO: 19). The open reading frame ofthis cDNA, nucleotides 65 to 799 of SEQ ID NO: 19, encodes a 245 aminoacid transmembrane protein (FIG. 17; SEQ ID NO: 20).

[0273] The signal peptide prediction program SIGNALP (Nielsen, et al.(1997) Protein Engineering 10:1-6) predicted that human TANGO 281includes an 38 amino acid signal peptide (amino acid 1 to amino acid 38of SEQ ID NO: 20) preceding the mature TANGO 281 protein (correspondingto amino acid 39 to amino acid 245 of SEQ ID NO: 20). The molecularweight of TANGO 281 without post-translational modifications is 26.5 kDaprior to the cleavage of the signal peptide, 20.2 kDa after cleavage ofthe signal peptide.

[0274] Human TANGO 281 is a transmembrane protein which contains one ormore of the following domains: (1) an extracellular domain; (2) atransmembrane domain; and (3) a cytoplasmic domain. The human TANGO 281protein contains an extracellular domain at amino acids 1 to 123 or amature extracellular domain at about amino acid residues 39 to 123, atransmembrane domain at amino acid residues 124 to 148, and acytoplasmic domain at amino acid residues 149 to 245 of SEQ ID NO: 20.

[0275]FIG. 18 depicts a hydropathy plot of human TANGO 281, the detailsof which are described herein. The dashed vertical line separates thesignal sequence (amino acids 1 to 38 of SEQ ID NO: 20) on the left fromthe mature protein (amino acids 38 to 245 of SEQ ID NO: 20) on theright.

[0276] Human TANGO 281 comprises photosystem II 10 kD phosphoprotein(PSBH) domain sequences, which have been shown to be phosphorylated in alight-dependent reaction, from amino acids 41 to 90 and 127 to 182 ofSEQ ID NO: 20. FIG. 19 depicts an alignment between the PSBH domain (SEQID NO: 46; Accession No. PF00737) and human TANGO 281 from amino acids97 to 146 of SEQ ID NO: 20.

[0277] An N-glycosylation site having the sequence NTTT is present inTANGO 281 at about amino acids 160 to 163 of SEQ ID NO: 48. Two proteinkinase C phosphorylation sites are present in human TANGO 281. The firsthas the sequence SVR (at amino acids 8 to 10), and the second has thesequence SSR (at amino acids 87 to 89). Three casein kinase IIphosphorylation sites are present in human TANGO 281. The first has thesequence SIPE (at amino acids 49 to 52), the second has the sequenceSCPD (at amino acids 53 to 56), and the third has the sequence SSLD (atamino acids 108 to 111). Human TANGO 281 has two N-myristylation sites.The first has the sequence GSCSSQ (at amino acids 60 to 65), and thesecond has the sequence GATVAI (at amino acids 119 to 124).

[0278] Nucleic acid base pairs 413 to 746 of human TANGO 281 (SEQ ID NO:19) have 81% identity to the nucleic acid sequence identified asAccession Number AV34245. Nucleic acid base pairs 438 to 746 of humanTANGO 281 (SEQ ID NO: 19) have 80% identity to a nucleic acid sequencereferred to as “gene 31” described in PCT Publication No. WO 98/39446(SEQ ID NO: 49). “Gene 31” is characterized as being expressed primarilyin brain and thymus, and to a lesser extent in such organs as liver,skin, bone and bone marrow.

[0279] Clone EpT281 was deposited with the American Type CultureCollection (10801 University Boulevard, Manassas, Va. 20110-2209) onApr. 21, 1999 and assigned Accession Number 207222. This deposit will bemaintained under the terms of the Budapest Treaty on the InternationalRecognition of the Deposit of Microorganisms for the Purposes of patentProcedure. This deposit was made merely as a convenience for those ofskill in the art and is not an admission that a deposit is requiredunder 35 U.S.C. § 112.

[0280] Mouse TANGO 281

[0281] A cDNA encoding mouse TANGO 281 was identified in a normal mousemegakaryocyte library by performing expression profiling onmegakarocytes obtained from mice with a the deletion of the element ofthe gata-1 gene responsible for megakaryocyte-specific expression. Thisanalysis led to the identification of a clone, Atmea49d3, encoding mouseTANGO 281. The mouse TANGO 281 cDNA of this clone is 1858 nucleotideslong (FIG. 20; SEQ ID NO: 21). The open reading frame of this cDNA,nucleotides 90 to 728 of SEQ ID NO: 21, encodes a 213 amino acidtransmembrane protein (FIG. 20; SEQ ID NO: 22).

[0282] The signal peptide prediction program SIGNALP (Nielsen, et al.(1997) Protein Engineering 10:1-6) predicted that mouse TANGO 281includes an 26 amino acid signal peptide (amino acid 1 to amino acid 26of SEQ ID NO: 22) preceding the mature TANGO 281 protein (correspondingto amino acid 27 to amino acid 213 of SEQ ID NO: 22). The molecularweight of mouse TANGO 281 without post-translational modifications is22.9 kDa prior to the cleavage of the signal peptide, 20.2 kDa aftercleavage of the signal peptide.

[0283] Mouse TANGO 281 is a transmembrane protein which contains one ormore of the following domains: (1) an extracellular domain; (2) atransmembrane domain; and (3) a cytoplasmic domain. The mouse TANGO 281protein contains an extracellular domain at amino acid residues 27 to112, a transmembrane domain at amino acid residues 113 to 137, and acytoplasmic domain at amino acid residues 138 to 213 of SEQ ID NO: 22.

[0284]FIG. 21 depicts a hydropathy plot of mouse TANGO 281, the detailsof which are described herein. The dashed vertical line separates thesignal sequence (amino acids 1 to 26 of SEQ ID NO: 22) on the left fromthe mature protein (amino acids 27 to 213 of SEQ ID NO: 22) on theright.

[0285] Mouse TANGO 281 comprises photosystem II 10 kD phosphoprotein(PSBH) domain sequences, which have been shown to be phosphorylated in alight-dependent reaction, from amino acids 42 to 91 and 128 to 183 ofSEQ ID NO: 22. Two N-glycosylation sites having the sequences NTTT (atamino acids 149 to 152) and NASS (at about amino 189 to 192) are presentin TANGO 281. A glycosaminoglycan attachment site having the sequenceSGFG is present in mouse TANGO 281, and protein kinase C phosphorylationsite having the sequence SSR is present in mouse TANGO 281. Two caseinkinase II phosphorylation sites are present in human TANGO 281. Thefirst has the sequence TPAE (at amino acids 80 to 83), and the secondhas the sequence SSFD (at amino acids 97 to 100). Mouse TANGO 281 hastwo N-myristylation sites. The first has the sequence GSCSNQ (at aminoacids 48 to 53), and the second has the sequence GATVAI (at amino acids108 to 113).

[0286] Northern blot analysis of mouse TANGO 281 expression revealed twomRNA bands, one of approximately 1.8 kb and another approximately 1.4kb. Expression of the 1.8 kb band was detected in the heart, spleen,lung and kidney, with the greatest abundance detected in the heart andlung, followed by the kidney and trace amounts in the spleen. Expressionof the 1.4 kb band was detected in the brain, spleen, and lung.Expression of the 1.4 kb and 1.8 kb species of mouse TANGO 281 wasdetected in 7 day old normal mouse embryos. Neither the 1.4 kb or the1.8 kb species of mouse TANGO 281 were detected in 11 day old normalmouse embryos. The 1.8 kb species of mouse TANGO 281 was detected in 15day old normal mouse embryos at 20% the level detected in 7 day oldnormal mouse embryos. Expression of the 1.8 kb species detected in 17day old normal mouse embryos was comparable to the level of expressiondetected in 7 day old normal mouse embryos. Expression of mouse TANGO281 expression was greatly reduced in megakaryocytes obtained fromgata-1 knockout mice.

[0287] In situ tissue screening was performed on mouse adult andembryonic tissues to analyze for the expression of mouse TANGO 281 MRNA.Mouse TANGO 281 expression was detected predominantly in the adultlymphoid tissues such as the thymus, lymph node, and spleen. Inparticular, mouse TANGO 281 expression was detected in the followingadult tissues: a moderate, ubiquitous signal was detected in thesubmandibular gland; a strong, ubiquitous signal was detected in theadrenal gland; a strong, multifocal signal was detected in the medullaof the thymus and a moderate, ubiquitous signal was detected in thecortex of the thymus; a strong signal was detected in the lymph node; astrong signal was detected in the follicles of the spleen; a weak signalwas detected in the mucosal epithelium of the bladder; a strong signalwas detected in the ovaries; a ubiquitous signal was detected in theplacenta; a moderate signal was detected in the muscle region of thestomach; a weak signal in a pattern outlining many of the large airwayswas detected in lung; a weak, ubiquitous signal was detected in theliver; and a weak, ubiquitous signal was detected in the kidney.

[0288] In the case of embryonic expression, mouse TANGO 281 expressionwas detected in the lung, stomach, thymus and submaxillary gland. Inparticular, at E16.5 a weak to moderate signal was detected in theintestine and stomach, and a moderate, ubiquitous signal was detected inthe lung. At P1.5, a signal was detected in the lung, stomach, thymus,and submaxillary gland.

[0289]FIG. 22 depicts that there is an overall 66.5% identity betweenthe precursor human TANGO 281 amino acid sequence and the precursormouse TANGO 281 amino acid sequence.

[0290] Clone EpT281 was deposited with the American Type CultureCollection (10801 University Boulevard, Manassas, Va. 20110-2209) onJun. 15, 1999 and assigned patent deposit Number PTA-224. This depositwill be maintained under the terms of the Budapest Treaty on theInternational Recognition of the Deposit of Microorganisms for thePurposes of patent Procedure. This deposit was made merely as aconvenience for those of skill in the art and is not an admission that adeposit is required under 35 U.S.C. §112.

[0291] Uses of TANGO 281 Nucleic Acids Polypeptides, and ModulatorsThereof

[0292] As TANGO 281 was originally found in a megakaryocyte library,TANGO 281 nucleic acids, proteins, and modulators thereof can be used tomodulate the proliferation, differentiation, and/or function ofmegakaryocytes and platelets. TANGO 281 nucleic acids, proteins, andmodulators thereof can be used to treat associated hematologicaldiseases such as thrombocytopenia, platelet disorders and bleedingdisorders (e.g., hemophilia). TANGO 281 nucleic acids, proteins, andmodulators thereof can be used to modulate platelet aggregation anddegranulation. Further, as TANGO 281 expression varies in mouse embryosduring development, TANGO 281 nucleic acids, proteins, and modulatorsthereof can be used to modulate the development of cells, tissues ororgans in embryos.

[0293] As TANGO 281 expression is greatly reduced in megakaryocytesobtained from gata-1 knockout mice compared normal mice, TANGO 281 iseither a direct or indirect target of gata-1 and has profound biologicalimplications. Gata-1 is a transcription factor involved in thedevelopment of hemapoietic cell lineages. Gata-1 expression is requiredfor proper development of erythocytes and megakaryocytes. Althoughdeletion of the gata-1 gene is lethal at the embryonic stage due to afailure to form red blood cells, deletion of only the element of thegata-1 gene responsible for megakaryocyte-specific expression (a 10 kbregion of genomic DNA containing a megakaryocyte specific DNase Ihypersensitive) is not lethal and results in a reduction in gata-1expression in the megakaryocyte without affecting gata-1 expression inred blood cells. The megakaryocytes of mice with this element of thegata-1 gene knocked out fail to develop into mature platelets, and themice experience abnormal bleeding due to their profoundthrombocytopenia. TANGO 281 nucleic acids, proteins, and modulatorsthereof can be used to treat disease and/or disorders associated withgata-1 dysfunction. In light of the reduced expression of TANGO 281 ingata-1 knockout mice, TANGO 281 expression can be utilized as a markerfor modulators of gata-1 expression and/or activity.

[0294] As TANGO 281 is expressed in the heart, brain, spleen, lung,kidney, embryo and megakaryocytes, TANGO 281 nucleic acids, proteins,and modulators thereof can be used to treat disorders of these cells,tissues, or organs, e.g., ischemic heart disease or atherosclerosis,head trauma, brain cancer, splenic lymphoma, splenomegaly, lung cancer,cystic fibrosis, rheumatoid lung disease, glomerulonephritis, end stagerenal disease, uremia, DiGeorge syndrome, thymoma, autoimmune disorders,atresia, Crohns's disease, and various embryonic disorders. TANGO 281nucleic acids, proteins, and modulators thereof can be used to modulatethe bleeding associated with uremia. Further, TANGO 281 nucleic acids,proteins, and modulators thereof can be used to treat hypercoagulationassociated with a damaged endothelium, e.g., pre-eclampsia, malignanthypertension, disseminated intravascular coagulopathy, renal transplantrejection, cyclosporin toxicity, microangiopathic hemolytic anemia, andthrombotic thrombocytopenic purpura.

[0295] Further, as TANGO 281 exhibits expression in the heart, TANGO 281nucleic acids, proteins, and modulators thereof can be used to treatheart disorders, e.g., atherosclerosis, hypertension, hypotension,angina pectoris, cardiomyopathy, and congenital heart disease.

[0296] As TANGO 281is expressed in lung, TANGO 281 nucleic acids,proteins, and modulators thereof can be used to modulate theproliferation, activation, development, differentiation, and/or functionof lung cells. Thus, TANGO 281 polypeptides, nucleic acids, ormodulators thereof, can be used to treat pulmonary (lung) disorders,such as atelectasis, pulmonary congestion or edema, chronic obstructiveairway disease (e.g., emphysema, chronic bronchitis, bronchial asthma,and bronchiectasis), diffuse interstitial diseases (e.g., sarcoidosis,pneumoconiosis, hypersensitivity pneumonitis, Goodpasture's syndrome,idiopathic pulmonary hemosiderosis, pulmonary alveolar proteinosis,desquamative interstitial pneumonitis, chronic interstitial pneumonia,fibrosing alveolitis, hamman-rich syndrome, pulmonary eosinophilia,diffuse interstitial fibrosis, Wegener's granulomatosis, lymphomatoidgranulomatosis, and lipid pneumonia), or tumors (e.g., bronchogeniccarcinoma, bronchiolovlveolar carcinoma, bronchial carcinoid, hamartoma,and mesenchymal tumors).

[0297] TANGO 281 exhibits homology to a gene referred to as “gene 31”(PCT Publication No. WO98/39446), which is expressed primarily in thebrain and thymus. In light of this, TANGO 281 nucleic acids, proteinsand modulators thereof can be utilized to ameliorate at least onesymptom associated with central nervous (CNS) disorders, hematopoieticdisorder, and disorders of the endocrine system.

[0298] In another example, as TANGO 281 exhibits homology to “gene 31”which is expressed in the brain and thymus, TANGO 281 polypeptides,nucleic acids, or modulators thereof, can be used to treat disorders ofthe brain, such as cerebral edema, hydrocephalus, brain herniations,iatrogenic disease (due to, e.g., infection, toxins, or drugs),inflammations (e.g., bacterial and viral meningitis, encephalitis, andcerebral toxoplasmosis), cerebrovascular diseases (e.g., hypoxia,ischemia, and infarction, intracranial hemorrhage and vascularmalformations, and hypertensive encephalopathy), and tumors (e.g.,neuroglial tumors, neuronal tumors, tumors of pineal cells, meningealtumors, primary and secondary lymphomas, intracranial tumors, andmedulloblastoma), and to treat injury or trauma to the brain.

[0299] Further, in light of TANGO 281's pattern of expression in mice,TANGO 281 expression can be utilized as a marker for specific tissues(e.g., lymphoid tissues such as the thymus and spleen) and/or cells(e.g., lymphocytes) in which INTERCEPT 281 is expressed. TANGO 281nucleic acids can also be utilized for chromosomal mapping.

[0300] A236 (Intercept 236)

[0301] The present invention is also based, at least in part, on thediscovery of cDNA molecules encoding A236, all of which are predicted tobe either wholly secreted or transmembrane proteins.

[0302] Members of the A236 family may have common structural domains.For example, A236 family members include a signal sequence. In oneembodiment, a A236 protein contains a signal sequence of amino acids1-18 of SEQ ID NO: 24. The signal sequence is cleaved during processingof the mature protein. In certain embodiments, an A236 family member hasthe amino acid sequence of SEQ ID NO: 24, and the signal sequence islocated at amino acids 1 to 16, 1 to 17, 1 to 18, 1 to 19 or 1 to 20. Insuch embodiments of the invention, the domains and the mature proteinresulting from cleavage of such signal peptides are also includedherein. For example, the cleavage of a signal sequence consisting ofamino acids 1 to 18 results in a mature A236 protein corresponding toamino acids 19 to 373 of SEQ ID NO: 24. The signal sequence is normallycleaved during processing of the mature protein.

[0303] In another example, A236 family members also include one or moreof the following domains: (1) an extracellular domain; (2) atransmembrane domain; and (3) a cytoplasmic domain.

[0304] A236 family members can include a immunoglobulin domain.Immunoglobulin domains are present in a variety of proteins and areinvolved in protein-protein and protein-ligand interaction. A consensusimmunoglobulin domain has the sequence of SEQ ID NO: 64. This consensussequence is shown in FIG. 23 where the more conserved residues in theconsensus sequence are indicated by uppercase letters and the lessconserved residues in the consensus sequence are indicated by lowercaseletters. The immunoglobulin domains of human A236 are located at aminoacids 28-113 and amino acids 146-210 of SEQ ID NO: 24. Theimmunoglobulin domains of mouse A236 are located at amino acids 27-112and amino acids 145-209 of SEQ ID NO: 26.

[0305] Human A236

[0306] A cDNA encoding human A236 was identified by analyzing thesequences of clones present in a human osteoblast CDNA library.

[0307] This analysis led to the identification of a clone, fthwa195d06,encoding human A236. The cDNA of this clone is 1948 nucleotides long(FIG. 23; SEQ ID NO: 23). The 1119 nucleotide open reading frame of thiscDNA, nucleotides 314-1432 of SEQ ID NO: 23, encodes a 373 amino acidprotein (FIG. 23; SEQ ID NO: 24).

[0308] In one embodiment of a nucleotide sequence of human A236 thenucleotide at position 379 is a guanine (G). In this embodiment, theamino acid at position 22 is glutamate (E). In another embodiment of anucleotide sequence of human A236, the nucleotide at position 379 is acytosine (C). In this embodiment, the amino acid at position 22 isaspartate (D). In another embodiment of a nucleotide sequence of mouseA236, the nucleotide at position 397 is a guanine (G). In thisembodiment, the amino acid at position 28 is a glutamate (E). In anotherembodiment of a nucleotide sequence of human A236, the nucleotide atposition 397 is a cytosine (C). In this embodiment, the amino acid atposition 28 is aspartate (D). In another embodiment of a nucleotidesequence of human A236, the nucleotide at position 400 is an adenine(A). In this embodiment, the amino acid at position 29 is a glutamate(E). In another embodiment of a nucleotide sequence of human A236, thenucleotide at position 400 is a cytosine (C). In this embodiment, theamino acid at position 29 is aspartate (D).

[0309] The presence of a methionine residue at amino acid residuepositions 200, 233, and 362 of SEQ ID NO: 24 indicate that there can bealternative forms of human A236 of 174 amino acids, 141 amino acids, and12 amino acids of SEQ ID NO: 24, respectively.

[0310] Another embodiment of the invention includes isolated nucleicacid molecules comprising a polynucleotide having a nucleotide sequenceencoding the polypeptide having the human A236 amino acid sequence inSEQ ID NO: 24, but lacking the N-terminal methionine residue. In thisembodiment, the nucleotide sequence of human A236, nucleotides 317-1432of SEQ ID NO: 23, encodes a human A236 amino acid sequence comprisingamino acids 2-373 of SEQ ID NO: 24.

[0311] The signal peptide prediction program SIGNALP (Nielsen et al.(1997) Protein Engineering 10:1-6) predicted that human A236 includes an18 amino acid signal peptide (amino acid 1 to about amino acid 18 of SEQID NO: 24) preceding the mature human A236 protein (corresponding toabout amino acid 19 to amino acid 373 of SEQ ID NO: 24).

[0312] In one embodiment, human A236 has an extracellular domain whichextends from about amino acid 19 to about amino acid 230, atransmembrane domain which extends from about amino acid 231 to aboutamino acid 255, and a cytoplasmic domain which extends from about aminoacid 256 to amino acid 373 of SEQ ID NO: 24. Alternatively, in anotherembodiment, a human A236 protein contains an extracellular domain atamino acid residues to 256 to 373, a transmembrane domain at amino acidresidues 231 to 255, and a cytoplasmic domain at amino acid residues 19to 230 of SEQ ID NO: 24.

[0313] Human A236 includes immunoglobulin domains at amino acids 28-113of SEQ ID NO: 24 and amino acids 146-210 of SEQ ID NO: 24. FIG. 25depicts an alignment of the immunoglobulin domains of human A236 with aconsensus immunoglobulin domain derived from a hidden Markov model (SEQID NO: 50).

[0314] Human A236 that has not been post-translationally modified ispredicted to have a molecular weight of 41.2 kDa prior to cleavage ofits signal peptide and a molecular weight of 39.2 kDa subsequent tocleavage of its signal peptide.

[0315] N-glycosylation sites are present at amino acids 74-77, 197-200,and 352-355. Protein kinase C phosphorylation sites are present at aminoacids 67-69, 110-112, 116-118, 296-298, 303-305, and 314-316. Caseinkinase II phosphorylation sites are present at amino acids 19-22, 54-57,157-160, 183-186, and 354-357. Tyrosine kinase phosphorylation sites arepresent at amino acids amino acids 102-109 and 257-264. N-myristoylationsites are present at amino acids 15-20, 146-151, 204-209, 211-216,232-237, 240-245, 293-298, and 300-305.

[0316] Clone fthwa195d06, which encodes human A236, was deposited asINTERCEPT 236 with the American Type Culture Collection (10801University Boulevard, Manassas, Va. 20110-2236) on May 7, 1999 andassigned Accession Number PTA-34. This deposit will be maintained underthe terms of the Budapest Treaty on the International Recognition of theDeposit of Microorganisms for the Purposes of patent Procedure. Thisdeposit was made merely as a convenience for those of skill in the artand is not an admission that a deposit is required under 35 U.S.C. §112.

[0317]FIG. 24 depicts a hydropathy plot of human A236, the details ofwhich are described herein. The hydropathy plot indicates the presenceof a signal sequence at the amino-terminus of human A236 and atransmembrane domain within human A236, suggesting that human A236 is atransmembrane protein.

[0318] When A236 was expressed in 293T cells the cells were found tosecrete a 30 kD form of A236. Briefly, 293T cells (8×10⁵ 293Tcells/well) were plated and incubated in growth medium (DMEM, 10% FBS,P/S) at 37° C., 5% CO2 overnight. The cells were then transfected withan expression vector capable of expressing human A236. The transfectionwas performed according to the LipofectAMINE protocol (Gibco/BRL;Gaithersburg, MD) using 2 mg DNA and 1 0ml LipofectAMINE for each well.After the cells were transfected for 5 hrs, the culture supernatant wasreplaced with fresh growth medium, and the cells were incubatedovernight. Next, the cells were pulse labeled as follows. The cells werewashed twice with DMEM lacking methionine and cysteine. Next, 1 ml DMEMlacking methionine and cysteine and 50 mCi Trans-35S (ICN Cat #51006)was added to each well. After incubation, 150 ml samples of cell culturesupernatant were collected and mixed with an equal amount of 2×SDS gelsample buffer. The samples were boiled for 5 mins and then separated bySDS PAGE.

[0319] Mouse A236

[0320] A cDNA encoding mouse A236 was identified by analyzing thesequences of clones present in a mouse osteoblast cDNA library. Theoriginal mouse clone, jymuf004e01, was derived from lung.

[0321] This analysis led to the identification of a clone, jymuf004e01,encoding mouse A236. The cDNA of this clone is 1949 nucleotides long(FIG. 26; SEQ ID NO: 25). The 1119 nucleotide open reading frame of thiscDNA, nucleotides 304 to 1422 of SEQ ID NO: 25, encodes a 373 amino acidprotein (FIG. 26; SEQ ID NO: 26).

[0322] In one embodiment of a nucleotide sequence of mouse A236 thenucleotide at position 366 is a guanine (G). In this embodiment, theamino acid at position 21 is glutamate (E). In another embodiment of anucleotide sequence of mouse A236, the nucleotide at position 366 is acytosine (C). In this embodiment, the amino acid at position 21 isaspartate (D). In another embodiment of a nucleotide sequence of mouseA236, the nucleotide at position 384 is a guanine (G). In thisembodiment, the amino acid at position 27 is a glutamate (E). In anotherembodiment of a nucleotide sequence of mouse A236, the nucleotide atposition 384 is a cytosine (C). In this embodiment, the amino acid atposition 27 is aspartate (D). In another embodiment of a nucleotidesequence of mouse A236, the nucleotide at position 387 is an adenine(A). In this embodiment, the amino acid at position 28 is a glutamate(E). In another embodiment of a nucleotide sequence of mouse A236, thenucleotide at position 387 is a cytosine (C). In this embodiment, theamino acid at position 28 is aspartate (D).

[0323] The presence of a methionine residue at amino acid residuepositions 199, and 232 of SEQ ID NO: 26 indicate that there can bealternative forms of mouse A236 of 175 amino acids, and 142 amino acidsof SEQ ID NO: 26, respectively.

[0324]FIG. 29 depicts a hydropathy plot of mouse A236, the details ofwhich are described herein.

[0325] Another embodiment of the invention includes isolated nucleicacid molecules comprising a polynucleotide having a nucleotide sequenceencoding the polypeptide having a mouse A236 amino acid sequence in SEQID NO: 26, but lacking the N-terminal methionine residue. In thisembodiment, the nucleotide sequence of mouse A236, nucleotides 317 to1432 of SEQ ID NO: 25, encodes the mouse A236 amino acid sequencecomprising amino acids 2 to 373 of SEQ ID NO: 26.

[0326] The signal peptide prediction program SIGNALP (Nielsen et al.(1997) Protein Engineering 10:1-6) predicted that mouse A236 includes an17 amino acid signal peptide (amino acid 1 to about amino acid 17 of SEQID NO: 26) preceding the mature mouse A236 protein (corresponding toabout amino acid 18 to amino acid 373 of SEQ ID NO: 26).

[0327] In one embodiment, mouse A236 has an extracellular domain whichextends from about amino acid 18 to about amino acid 229, atransmembrane domain which extends from about amino acid 230 to aboutamino acid 254, and a cytoplasmic domain which extends from about aminoacid 255 to amino acid 373of SEQ ID NO: 26. Alternatively, in anotherembodiment, a mouse A236 protein contains an extracellular domain atamino acid residues 255 to 373, a transmembrane domain at amino acidresidues 230 to 254, and a cytoplasmic domain at amino acid residues 18to 229 of SEQ ID NO: 26.

[0328] Mouse A236 that has not been post-translationally modified ispredicted to have a molecular weight of 41.2 kDa prior to cleavage ofits signal peptide and a molecular weight of 39.2 kDa subsequent tocleavage of its signal peptide.

[0329] Mouse A236 includes immunoglobulin domains at amino acids 27-112and amino acids 145-209 of SEQ ID NO: 26.

[0330] A casein kinase II phosphorylation site is present at amino acids18-21, 53-56, 182-185, and 354-357 of SEQ ID NO: 157, respectively.N-myristoylation sites are present at amino acids 14-19, 145-150, 203,208, 210, 215, 231-236, and 239-244, respectively. Protein kinase Cphosphorylation sites are present at amino acids 66-68, 109-111,115-117, 295-297, 302-304, and 313-315 of SEQ ID NO: 157, respectively.A cyclic AMP phosphorylation site and cGMP-dependent protein kinasephosphorylation site is present at amino acids 256-259 of SEQ ID NO:157. ASN-glycosylation and N glycosylation sites are present at aminoacids 73-76, and 196-199, respectively. A tyrosine kinasephosphorylation site is present at amino acids 101-108.

[0331] In situ tissue screening was performed on mouse adult andembryonic tissue to analyze the expression of mouse A236 mRNA. Insummary, mouse A236 mRNA expression was detected by in situhybridization in a few adult and numerous embryonic tissues. Adultexpression was detected ubiquitously in brain and more restricted inplacenta, uterus, and ovary. Embryonic expression was nearly ubiquitouswith higher expression in brain, mandible, and the intestinal tract.Liver noticeably lacked expression during embryogenesis.

[0332] Human and mouse A236 sequences exhibit considerable similarity atthe protein, nucleic acid, and open reading frame levels. An alignment(made using the ALIGN software (Myers and Miller (1989) CABIOS, ver.2.0); BLOSUM 62 scoring matrix; gap penalties-12/-4), reveals a proteinidentity of 92.5%. The human and mouse A236 full length cDNAs are 83.57%identical, as assessed using the same software and parameters asindicated. In the respective ORFs, calculated in the same fashion as thefull length cDNAs, human and mouse A236 are 87.81% identical. Thenucleotide sequence (ORF) and amino acid sequence alignments of humanand mouse A236 can be found in FIG. 27, and FIG. 28, respectively.

[0333] Use of A236 Nucleic Acids, Polypeptides and Modulators Thereof

[0334] A236 polypeptides, nucleic acids, and modulators thereof, can beused to modulate the function, morphology, proliferation and/ordifferentiation of cells in the tissues in which it is expressed. Inaddition, based on its homology to CAR (Bergelson et al. (1997) Science275:1320-23) A236 may act as a entry mediator for coxsackie B virusesand adenovirus. Thus, compounds which interfere with virus binding toA236 or compounds which reduce A236 expression can be used to interferewith viral entry. A236 polypeptides, nucleic acids, and modulatorsthereof can be used to treat or prevent disorders associated withinfection by the coxsackie B viruses and adenovirus, e.g., cardiacinfection (e.g., myocarditis or dilated cardiomyopathy), central nervoussystem infection (e.g., non-specific febrile illness ormeningoencephalitis), pancreatic infection (e.g., acute pancreatitis),respiratory infection (pneumonia), gastrointestinal infection, or type Idiabetes.

[0335] As human A236 was originally found in a LPS stimulated humanprimary osteoblast library, A236 nucleic acids, proteins, and modulatorsthereof can be used to modulate the proliferation, differentiation,and/or function of cells that form bone matrix, e.g., osteoblasts andosteoclasts, and can be used to modulate the formation of bone matrix.Thus, A236 nucleic acids, proteins, and modulators thereof can be usedto treat cartilage and bone associated diseases and disorders, and canplay a role in bone growth, formation, and remodeling. Examples ofcartilage and bone associated diseases and disorders include, e.g., bonecancer, achondroplasia, myeloma, fibrous dysplasia, scoliosis,osteoarthritis, osteosarcoma, and osteoporosis.

[0336] As the original mouse A236 clone, jymuf004e01, was derived fromlung, A236 nucleic acids, proteins, and modulators thereof can be usedto modulate the proliferation, activation, development, differentiation,and/or function of lung cells. Thus, A236 polypeptides, nucleic acids,or modulators thereof, can be used to treat pulmonary (lung) disorders,such as atelectasis, pulmonary congestion or edema, chronic obstructiveairway disease (e.g., emphysema, chronic bronchitis, bronchial asthma,and bronchiectasis), diffuse interstitial diseases (e.g., sarcoidosis,pneumoconiosis, hypersensitivity pneumonitis, Goodpasture's syndrome,idiopathic pulmonary hemosiderosis, pulmonary alveolar proteinosis,desquamative interstitial pneumonitis, chronic interstitial pneumonia,fibrosing alveolitis, hamman-rich syndrome, pulmonary eosinophilia,diffuse interstitial fibrosis, Wegener's granulomatosis, lymphomatoidgranulomatosis, and lipid pneumonia), or tumors (e.g., bronchogeniccarcinoma, bronchiolovlveolar carcinoma, bronchial carcinoid, hamartoma,and mesenchymal tumors).

[0337] A236 polypeptides, nucleic acids, and modulators thereof, can beused to modulate the function, morphology, proliferation and/ordifferentiation of cells in the tissues in which it is expressed. Suchmolecules can be used to treat disorders associated with abnormal oraberrant metabolism or function of cells in the tissues in which it isexpressed. Tissues in which A236 is expressed include, for example,brain, placenta, uterus, ovaries, intestinal tract and the heart.

[0338] In another example, A236 polypeptides, nucleic acids, ormodulators thereof, can be used to treat disorders of the brain, such ascerebral edema, hydrocephalus, brain herniations, iatrogenic disease(due to, e.g., infection, toxins, or drugs), inflammations (e.g.,bacterial and viral meningitis, encephalitis, and cerebraltoxoplasmosis), cerebrovascular diseases (e.g., hypoxia, ischemia, andinfarction, intracranial hemorrhage and vascular malformations, andhypertensive encephalopathy), and tumors (e.g., neuroglial tumors,neuronal tumors, tumors of pineal cells, meningeal tumors, primary andsecondary lymphomas, intracranial tumors, and medulloblastoma), and totreat injury or trauma to the brain.

[0339] In another example, A236 polypeptides, nucleic acids, ormodulators thereof, can be used to treat pancreatic disorders, such aspancreatitis (e.g., acute hemorrhagic pancreatitis and chronicpancreatitis), pancreatic cysts (e.g., congenital cysts, pseudocysts,and benign or malignant neoplastic cysts), pancreatic tumors (e.g.,pancreatic carcinoma and adenoma), diabetes mellitus (e.g., insulin- andnon-insulin-dependent types, impaired glucose tolerance, and gestationaldiabetes), or islet cell tumors (e.g., insulinomas, adenomas,Zollinger-Ellison syndrome, glucagonomas, and somatostatinoma).

[0340] Because A236 is expressed in the reproductive tract, particularlyin the ovaries, the A236 polypeptides, nucleic acids and/or modulatorsthereof can be used to modulate the function, morphology, proliferationand/or differentiation of cells in the tissues in which it is expressed.

[0341] For example, the A236 polypeptides, nucleic acids and/ormodulators thereof can be used modulate the function, morphology,proliferation and/or differentiation of the ovaries. For example, suchmolecules can be used to treat or modulate disorders associated with theovaries, including, without limitation, ovarian tumors, McCune-Albrightsyndrome (polyostotic fibrous dysplasia). For example, the A236polypeptides, nucleic acids and/or modulators can be used in thetreatment of infertility.

[0342] The A236 polypeptides, nucleic acids and/or modulators thereofcan be used to modulate the function, morphology, proliferation and/ordifferentiation of cells in the tissues of the reproductive tract otherthan the ovaries. For example, such molecules can be used to treat ormodulate disorders associated with the female reproductive tractincluding, without limitation, uterine disorders, e.g., hyperplasia ofthe endometrium, uterine cancers (e.g., uterine leiomyomoma, uterinecellular leiomyoma, leiomyosarcoma of the uterus, malignant mixedmullerian Tumor of uterus, uterine Sarcoma), and dysfunctional uterinebleeding (DUB).

[0343] In another example, A236 polypeptides, nucleic acids, ormodulators thereof, can be used to treat renal (kidney) disorders, suchas glomerular diseases (e.g., acute and chronic glomerulonephritis,rapidly progressive glomerulonephritis, nephrotic syndrome, focalproliferative glomerulonephritis, glomerular lesions associated withsystemic disease, such as systemic lupus erythematosus, Goodpasture'ssyndrome, multiple myeloma, diabetes, neoplasia, sickle cell disease,and chronic inflammatory diseases), tubular diseases (e.g., acutetubular necrosis and acute renal failure, polycystic renaldiseasemedullary sponge kidney, medullary cystic disease, nephrogenicdiabetes, and renal tubular acidosis), tubulointerstitial diseases(e.g., pyeloneplritis, drug and toxin induced tubulointerstitialnephritis, hypercalcemic nephropathy, and hypokalemic nephropathy) acuteand rapidly progressive renal failure, chronic renal failure,nephrolithiasis, vascular diseases (e.g., hypertension andnephrosclerosis, microangiopathic hemolytic anemia, atheroembolic renaldisease, diffuse cortical necrosis, and renal infarcts), or tumors(e.g., renal cell carcinoma and nephroblastoma).

[0344] In another example, A236 polypeptides, nucleic acids, ormodulators thereof, can be used to treat intestinal disorders, such asischemic bowel disease, infective enterocolitis, Crohn's disease, benigntumors, malignant tumors (e.g., argentaffinomas, lymphomas,adenocarcinomas, and sarcomas), malabsorption syndromes (e.g., celiacdisease, tropical sprue, Whipple's disease, and abetalipoproteinemia),obstructive lesions, hernias, intestinal adhesions, intussusception, orvolvulus.

[0345] Human TANGO 300

[0346] A cDNA encoding human TANGO 300 was identified by analyzing thesequences of clones present in a human fetal lung cDNA library.

[0347] This analysis led to the identification of a sequence encodinghuman TANGO 300. The cDNA of this clone is 1332 nucleotides long (FIG.30; SEQ ID NO: 27). The 1083 nucleotide open reading frame of this cDNA,nucleotide 31 to nucleotide 1113 of SEQ ID NO: 27, encodes a 361 aminoacid protein (FIG. 30; SEQ ID NO: 28).

[0348] The signal peptide prediction program SIGNALP (Nielsen et al.,1997, Protein Engineering 10:1-6) predicted that human TANGO 300includes a 20 amino acid signal peptide (amino acid 1 to about aminoacid 20 of SEQ ID NO: 28) preceding the mature human TANGO 300 protein(corresponding to about amino acid 21 to amino acid 361 of SEQ ID NO:28).

[0349] Human TANGO 300 is a transmembrane protein having anextracellular domain from about amino acid 21 to about amino acid 304, atransmembrane domain from about amino acid 305 to about amino acid 321,and a cytoplasmic domain from about amino acid 322 to amino acid 361 ofSEQ ID NO: 28.

[0350] Alternatively, in another embodiment, a human TANGO 300 proteincontains an extracellular domain at amino acid residues 322 to aminoacid 361, transmembrane domains at amino acid residues 305 to aboutamino acid 321, and a cytoplasmic domain at amino acid 21 to about aminoacid 304 of SEQ ID NO: 28.

[0351] Human TANGO 300 that has not been post-translationally modifiedis predicted to have a molecular weight of 40.6 kDa prior to cleavage ofits signal peptide and a molecular weight of 38.5 kDa subsequent tocleavage of its signal peptide.

[0352] Within human TANGO 300, protein kinase C phosphorylation sitesare present at amino acids 74 to 76, 89 to 91, 307 to 309, and 359 to361. Casein kinase II phosphorylation sites are present at amino acids34 to 37, 41 to 44, 74 to 77, 153 to 156, and 169 to 172. Tyrosinekinase phosphorylation sites are present at amino acids 111 to 117 and236 to 243. N-myristylation sites are present at amino acids 25 to 30and 170 to 175.

[0353] Clone AthX672i5, which encodes human TANGO 300, was deposited asEpT300 with the American Type Culture Collection (ATCC® 10801 UniversityBoulevard, Manassas, Va. 20110-2236) on Jun. 30, 1999 and assignedAccession Number PTA-293. This deposit will be maintained under theterms of the Budapest Treaty on the International Recognition of theDeposit of Microorganisms for the Purposes of patent Procedure. Thisdeposit was made merely as a convenience for those of skill in the artand is not an admission that a deposit is required under 35 U.S.C. §112.

[0354]FIG. 31 depicts a hydropathy plot of human TANGO 300, the detailsof which are described herein. The hydropathy plot indicates that humanTANGO 300 has a signal peptide at its amino terminus and an internalhydrophobic region, suggesting that human TANGO 300 is a transmembraneprotein.

[0355] Mouse TANGO 300

[0356] A clone, jthub009c07, containing mouse TANGO 300 was alsoidentified. The eDNA of this clone is 1400 nucleotides long (FIG. 32;SEQ ID NO: 29). The 1155 nucleotide open reading frame of this cDNA,nucleotide 41 to nucleotide 1195 of SEQ ID NO: 29, encodes a 385 aminoacid protein (FIG. 32; SEQ ID NO: 30).

[0357] The signal peptide prediction program SIGNALP (Nielsen et al.,1997, Protein Engineering 10:1-6) predicted that mouse TANGO 300includes a 19 amino acid signal peptide (amino acid 1 to about aminoacid 19 of SEQ ID NO: 30) preceding the mature mouse TANGO 300 protein(corresponding to about amino acid 20 to amino acid 385 of SEQ ID NO:30).

[0358] Mouse TANGO 300 is a transmembrane protein having anextracellular domain which extends from about amino acid 20 to aboutamino acid 318, a transmembrane domain which extends from about aminoacid 319 to about amino acid 335, and a cytoplasmic domain which extendsfrom about amino acid 336 to amino acid 385 of SEQ ID NO: 30.

[0359] Alternatively, in another embodiment, a mouse TANGO 300 proteincontains an extracellular domain at amino acid residues 336 to aminoacid 385, transmembrane domains at amino acid residues 319 to aboutamino acid 335, and a cytoplasmic domain at amino acid 20 to about aminoacid 318 of SEQ ID NO: 30.

[0360] Mouse TANGO 300 that has not been post-translationally modifiedis predicted to have a molecular weight of 43.1 kDa prior to cleavage ofits signal peptide and a molecular weight of 41.0 kDa subsequent tocleavage of its signal peptide.

[0361] Within mouse TANGO 300, protein kinase C phosphorylation sitesare present at amino acids 85 to 87 and 378 to 380. Casein kinase IIphosphorylation sites are present at amino acids 22 to 25, 37 to 40, 149to 152, 165 to 168 and 287 to 290. A tyrosine kinase phosphorylationsite is present at amino acids 107 to 113. N-myristylation sites arepresent at amino acids 29 to 34, 89 to 94, 166 to 171 and 207 to 212. AN-glycosylation site is present at amino acids 136 to 139.

[0362]FIG. 33 depicts a hydropathy plot of mouse TANGO 300, the detailsof which are described herein. The hydropathy plot indicates that mouseTANGO 300 has a signal peptide at its amino terminus and an internalhydrophobic region, suggesting that mouse TANGO 300 is a transmembraneprotein.

[0363]FIG. 34 depicts an alignment of the open reading frame (ORF)nucleotide sequence of human TANGO 300 (SEQ ID NO: 27) and the ORFnucleotide sequence of mouse TANGO 300 (SEQ ID NO: 29). This alignmentwas created using BESTFIT (BLOSUM 62 scoring matrix; gap open penalty of12; frame shift penalty of 5; gap extend penalty of 4). In thisalignment, the sequences are 77.7% identical. FIG. 35 depicts analignment of the amino acid sequence of human TANGO 300 (SEQ ID NO: 28)and the amino acid sequence of mouse TANGO 300 (SEQ ID NO: 30). Thisalignment was created using BESTFIT (BLOSUM 62 scoring matrix; gap openpenalty of 12; frame shift penalty of 5; gap extend penalty of 4). Inthis alignment, the sequences are 69.6% identical. The complete cDNAsequences of human and mouse TANGO 300 are 75.8% identical.

[0364] Use of TANGO 300 Nucleic Acids, Polypeptides, and ModulatorsThereof

[0365] TANGO 300 polypeptides, nucleic acids, and modulators thereof canbe used to modulate the function, morphology, proliferation and/ordifferentiation of cells in the tissues in which they are expressed.

[0366] Further, in light of TANGO 300's presence in a fetal lung cDNAlibrary, TANGO 300 expression can be utilized as a marker for specifictissues (e.g., lung) and/or cells (e.g.,pulmonary) in which TANGO 300 isexpressed. TANGO 300 nucleic acids can also be utilized for chromosomalmapping.

[0367] Human TANGO 353

[0368] A cDNA encoding human TANGO 353 was identified by analyzing thesequences of clones present in a mixed lymphocyte reaction library forsequences that encode a wholly secreted or transmembrane protein. Thisanalysis led to the identification of a clone, jthLa031g12 encodinghuman TANGO 353. The human TANGO 353 cDNA of this clone is 1239nucleotides long (FIG. 36; SEQ ID NO: 31). The open reading frame ofthis cDNA, nucleotides 76 to 765 of SEQ ID NO: 31, encodes a 230 aminoacid transmembrane protein (FIG. 36; SEQ ID NO: 32).

[0369]FIG. 37 depicts a hydropathy plot of human TANGO 353, the detailsof which are described herein.

[0370] The signal peptide prediction program SIGNALP (Nielsen et al.,1997, Protein Engineering 10:1-6) predicted that human TANGO 353includes a 14 amino acid signal peptide (amino acid 1 to amino acid 14of SEQ ID NO: 32) preceding the mature human TANGO 353 protein(corresponding to amino acid 15 to amino acid 230 of SEQ ID NO: 32). Themolecular weight of human TANGO 353 protein without post-translationalmodifications is 24.8 kDa prior to the cleavage of the signal peptideand 23.3 kDa after cleavage of the signal peptide. The presence of amethionine residue at positions 39, 170 and 184 indicates that there canbe alternative forms of human TANGO 353 of 192 amino acids, 61 aminoacids, and 47 amino acids of SEQ ID NO: 32, respectively.

[0371] Human TANGO 353 is a transmembrane protein which can include oneor more of the following domains: (1) an extracellular domain; (2) atransmembrane domain; and (3) a cytoplasmic domain. The human TANGO 353protein contains an extracellular domain at amino acid residues 15 to116, a transmembrane domain at amino acid residues 117 to 141, and acytoplasmic domain at amino acid residues 142 to 230 of SEQ II) NO: 32.

[0372] Alternatively, in another embodiment, a human TANGO 353 proteincontains a cytoplasmic domain at amino acid residues 15 to 116, atransmembrane domain at amino acid residues 117 to 141, and anextracellular domain at amino acid residues 142 to 230 of SEQ ID NO: 32.

[0373] In one embodiment, a TANGO 353 protein contains a signal sequenceof about amino acids 1 to 14 of SEQ ID NO: 32. In certain embodiments, aTANGO 353 family member has the amino acid sequence of SEQ ID NO: 32,and the signal sequence is located at amino acids 1 to 12, 1 to 13, 1 to14, 1 to 15 or 1 to 16. In such embodiments of the invention, theextracellular domain and the mature protein resulting from cleavage ofsuch signal peptides are also included herein. For example, the cleavageof a signal sequence consisting of amino acids 1 to 12 results in anextracellular domain consisting of amino acids 13 to 116 of SEQ ID NO:32 and the mature TANGO 353 protein corresponding to amino 13 to 230.

[0374] A TANGO 353 family member can include one or more of thefollowing domains: (1) an extracellular domain; (2) a transmembranedomain; and (3) a cytoplasmic domain. Thus, in one embodiment, an TANGO353 protein contains an extracellular domain of about amino acids 1 to116 of SEQ ID NO: 32, or a mature extracellular domain of about aminoacids 15 to 116 of SEQ ID NO: 32. In another embodiment, a TANGO 353protein contains a transmembrane domain of about amino acids 117 to 141of SEQ ID NO: 32. In another embodiment, a TANGO 353 protein contains acytoplasmic domain of about amino acids 142 to 230 of SEQ ID NO: 32. Inyet another embodiment, a TANGO 353 protein is a mature proteincontaining an extracellular, transmembrane and cytoplasmic domain ofabout amino acids 15 to 230 of SEQ I) NO: 32.

[0375] In one embodiment of a nucleotide sequence of human TANGO 353,the nucleotide at position 68 is thymine (T). In this embodiment, theamino acid at position 23 is valine (V). In an alternative embodiment, aspecies variant of human TANGO 353 has a nucleotide at position 68 whichis cytosine (C). In this embodiment, the amino acid at position 23 isalanine (A), i.e., a conservative substitution.

[0376] In one embodiment of a nucleotide sequence of human TANGO 353,the nucleotide at position 77 is adenine (A). In this embodiment, theamino acid at position 26 is tyrosine (Y). In an alternative embodiment,a species variant of human TANGO 353 has a nucleotide at position 77which is thymine (T). In this embodiment, the amino acid at position 26is phenylalanine (F), i.e., a conservative substitution.

[0377] In one embodiment of a nucleotide sequence of human TANGO 353,the nucleotide at position 203 is guanine (G). In this embodiment, theamino acid at position 68 is arginine (R). In an alternative embodiment,a species variant of human TANGO 353 has a nucleotide at position 203which is adenine (A). In this embodiment, the amino acid at position 68is histidine (H), i.e., a conservative substitution.

[0378] In one embodiment of a nucleotide sequence of human TANGO 353,the nucleotide at position 309 is cytosine (C). In this embodiment, theamino acid at position 103 is aspartate (D). In an alternativeembodiment, a species variant of human TANGO 353 has a nucleotide atposition 309 which is guanine (G). In this embodiment, the amino acid atposition 103 is glutamate (E), i.e., a conservative substitution.

[0379] Four N-glycosylation sites are present in human TANGO 353. Thefirst has the sequence NFTL (at amino acid residues 48 to 51), thesecond has the sequence NLSG (at amino acid residues 73 to 76), thethird has the sequence NQSQ (at amino acid residues 97 to 100), and thefourth has the sequence NVSF (at amino acid residues 109 to 112). HumanTANGO 353 has one cAMP- and cGMP-dependent protein kinasephosphorylation site with the sequence KRPT (at amino acid residues 209to 212). Five protein kinase C phosphorylation sites are present inhuman TANGO 353. The first has the sequence SIR (at amino acid residues19 to 21), the second has the sequence SSK (at amino acid residues 78 to80), the third has the sequence SAK (at amino acids 180 to 182), thefourth has the sequence TRK (at amino acid residues 207 to 209), and thefifth has the sequence TFR (at amino acid residues 225 to 227). HumanTANGO 353 has four casein kinase II phosphorylation sites. The first hasthe sequence SSQE (at amino acid residues 28 to 31), the second has thesequence TMPE (at amino acid residues 183 to 186), the third has thesequence TLDD (at amino acid residues 191 to 194), and the fourth hasthe sequence SSPE (at amino acid residues 216 to 219). Human TANGO 353has two N-myristylation sites. The first has the sequence GNFPGA (atamino acid residues 42 to 47) and the second has the sequence GVTFNL (atamino acid residues 69 to 74).

[0380] Clone EpT353, which encodes human TANGO 353, was deposited withthe American Type Culture Collection (10801 University Boulevard,Manassas, Va. 20110-2209) on Jun. 29, 1999 and assigned Accession NumberPTA-292. This deposit will be maintained under the terms of the BudapestTreaty on the International Recognition of the Deposit of Microorganismsfor the Purposes of patent Procedure. This deposit was made merely as aconvenience for those of skill in the art and is not an admission that adeposit is required under 35 U.S.C. §112.

[0381] Uses of TANGO 353 Nucleic Acids, Polypeptides, and ModulatorsThereof

[0382] As TANGO 353 was originally found in a mixed lymphocyte library,TANGO 353 nucleic acids, proteins, and modulators thereof can beutilized to diagnose disorders and/or modulate processes involved inlymphocyte development, differentiation and activity, including, but notlimited to development, differentiation and activation of T cells,including T helper, T cytotoxic and non-specific T killer cell types andsubtypes, and B cells, immune functions associated with such cells, andamelioration of one or more symptoms associated with abnormal functionof such cell types. Such disorders can include, but are not limited to,autoimmune disorders (e.g., autoimmune thyroiditis, Type I diabetesmellitus, insulin-resistant diabetes, autoimmune anemia, multiplesclerosis, rheumatoid arthritis, lupus or sclerodoma, allergy, includingallergic rhinitis and food allergies, asthma, psoriasis, graftrejection, transplantation rejection, graft versus host disease,pathogenic susceptibilities), inflammatory disorders (e.g., bacterial orviral infections, wound healing and inflammatory bowel disease andarthritis), apoptotic disorders, and cytotoxic disorders, septic shock,cachexia, and proliferative disorders (e.g., B cell cancers stimulatedby TNF).

[0383] Other TANGO 353 associated disorders can include TNF relateddisorders (e.g., acute myocarditis, myocardial infarction, congestiveheart failure, T cell disorders (e.g., dermatitis, fibrosis)),immunological differentiative and apoptotic disorders (e.g.,hyper-proliferative syndromes such as systemic lupus erythematosus(lupus)), and disorders related to angiogenesis (e.g., tumor formationand/or metastasis, cancer). Modulators of TANGO 353 expression and/oractivity can be used to treat such disorders.

[0384] As TANGO 353 is expressed in mixed lymphocyte cultures, and hencelikely expressed in bone marrow, TANGO 353 nucleic acids, proteins, andmodulators thereof can be used to diagnose disorders associated withcells in the bone marrow and/or modulate the proliferation,differentiation, and/or function of cells that appear in the bonemarrow, e.g., stem cells (e.g., hematopoietic stem cells), and bloodcells, e.g., erythrocytes, platelets, and leukocytes. Thus TANGO 353nucleic acids, proteins, and modulators thereof can be used to treatbone marrow, blood, and hematopoietic associated diseases and disorders,e.g., acute myeloid leukemia, hemophilia, leukemia, anemia (e.g., sicklecell anemia), and thalassemia.

[0385] As TANGO 353 is a transmembrane protein, TANGO 353 nucleic acids,proteins and modulators thereof can be utilized to modulateintercellular signaling cascades, or alternatively.

[0386] TANGO 353 expression can be utilized as a marker (e.g., an insitu marker) for specific tissues (e.g., spleen) and/or cells (e.g.,lymphocytes) in which TANGO 353 is expressed. TANGO 353 nucleic acidscan also be utilized for chromosomal mapping, or as chromosomal markers,e.g., in radiation hybrid mapping.

[0387] Human TANGO 393

[0388] A cDNA encoding human TANGO 393 was identified by analyzing thesequences of clones present in a human fetal hypothalamus cDNA libraryfor sequences containing signal peptides. This analysis led to theidentification of a clone, jthhb039f09, encoding full-length human TANGO393. The human cDNA of this clone is 1778 nucleotides long (FIG. 38; SEQID NO: 33). The open reading frame of this cDNA, nucleotides 40 to 1458of SEQ ID NO: 33, encodes a 473 amino acid human TANGO 393 transmembraneprotein (FIG. 38; SEQ ID NO: 34).

[0389]FIG. 39 depicts a hydropathy plot of human TANGO 393, the detailsof which are described herein. The dashed vertical line separates thesignal sequence (amino acids 1 to 26 of SEQ ID NO: 34) on the left fromthe mature protein (amino acids 27 to 473 of SEQ ID NO: 34) on theright.

[0390] The signal peptide prediction program SIGNALP (Nielsen, et al.(1997) Protein Engineering 10:1-6) predicted that human TANGO 393includes an 26 amino acid signal peptide (amino acid 1 to amino acid 26of SEQ ID NO: 34) preceding the mature protein (corresponding to aminoacid 27 to amino acid 473 of SEQ ID NO: 34). The molecular weight ofhuman TANGO 393 without post-translational modifications is 50.7 kDaprior to the cleavage of the signal peptide, 47.8 kDa after cleavage ofthe signal peptide. The presence of a methionine residue at position 229indicates that there can be alternative forms of human TANGO 393 of 245amino acids of SEQ ID NO: 34.

[0391] Human TANGO 393 is a transmembrane protein which contains one ormore of the following domains: (1) an extracellular domain; (2) atransmembrane domain; and (3) a cytoplasmic domain; and (4) aleucine-rich domain. The human TANGO 393 protein contains anextracellular domain at amino acids 27 to 447, a transmembrane domain atamino acid residues 448 to 467, and a cytoplasmic domain at amino acidresidues 468 to 473 of SEQ ID NO: 34.

[0392] Alternatively, in another embodiment, a human TANGO 393 proteincontains a cytoplasmic domain at amino acids 27 to 447, a transmembranedomain at amino acid residues 448 to 467, and a extracellular domain atamino acid residues 468 to 473 of SEQ ID NO: 34.

[0393] In another embodiment, human TANGO 393 protein contains a signalsequence of about amino acids 1 to 26 of SEQ ID NO: 34. In oneembodiment, a TANGO 393 protein contains an extracellular domain atamino acids 1 to about 447 of SEQ ID NO: 34 or a mature extracellulardomain at about amino acid residues 27 to 447, a transmembrane domain atabout amino acid residues 448 to 467, and a cytoplasmic domain at aboutamino acid residues 468 to 473 of SEQ ID NO: 34. In another embodiment,a TANGO 393 family member contains an extracellular domain at aminoacids 1 to about 26 or a mature extracellular domain at about amino acidresidues 27 to 449, a transmembrane domain at about amino acid residues450 to 467, and a cytoplasmic domain at about amino acid residues 468 to473 of SEQ ID NO: 34.

[0394] A TANGO 393 family member can include one or moreleucine-rich-repeat (LRR) domains. A leucine-rich-repeat domaintypically has the following degenerate consensus sequence:x-L-x-x-L-x-L-x-x-[NCT]-x-L-x-x-x-L-x-x-x-x-L-x-x-L, wherein L is aleucine residue and can be replaced by any aliphatic residue,“x” is anyamino acid, and [NCT] is either an asparagine, cysteine or threonine,respectively. Leucine-rich-repeat domains most frequently appear intandem repeats. The degenerate leucine-rich-repeat domains arecharacteristic of a diverse set of signaling proteins that are involvedin cell signaling, cell growth and cell differentiation. Defects inleucine-rich-repeat genes have been shown to cause various diseaseswhich include but are not limited to Bemard-Soulier disease, a bleedingdisorder. Furthermore, leucine-rich-repeat genes are involved in thepathogenesis of diseases, for example, the leucine-rich-repeat of type-1human immunodeficiency virus Rev protein is the trans-activating regionof the virus (Kobe and Deisenhofer, 1994, TIBS, 19:415-421).

[0395] In one embodiment, a TANGO 393 family member has the amino acidsequence of SEQ ID NO: 34 and, preferably, a leucine-rich-repeat domainconsensus sequence is located at about amino acid positions 26 to 57, 58to 81, 82 to 105, 106 to 130, 131 to 154, 155 to 178, 179 to 202, 203 to226, 227 to 250, and/or 260 to 310 of human TANGO 393 (SEQ ID NO: 34).In another embodiment, a TANGO 393 family member has the amino acidsequence of SEQ ID NO: 36 and, preferably, a leucine-rich-repeat domainis located at about amino acid positions 26 to 57, 58 to 81, 82 to 105,106 to 130, 131 to 154, 155 to 178, 179 to 202, 203 to 226, 227 to 250,and/or 260 to 310 of mouse TANGO 393 (SEQ ID NO: 36).

[0396] In another embodiment, a TANGO 393 family member includes one ormore leucine-rich-repeat domain consensus sequences having an amino acidsequence that is at least about 55%, preferably at least about 65%, morepreferably at least 75%, yet more preferably at least about 85%, andmost preferably at least about 95% identical to amino acids 26 to 57, 58to 81, 82 to 105, 106 to 130, 131 to 154, 155 to 178, 179 to 202, 203 to226, 227 to 250, and/or 260 to 310 of human TANGO 393 of SEQ ID NO: 34.In another embodiment, a TANGO 393 family member includes one or moreleucine-rich-repeat domains having an amino acid sequence that is atleast about 55%, preferably at least about 65%, more preferably at least75%, yet more preferably at least about 85%, and most preferably atleast about 95% identical to amino acid positions 26 to 57, 58 to 81, 82to 105, 106 to 130, 131 to 154, 155 to 178, 179 to 202, 203 to 226, 227to 250, and/or 260 to 310 of mouse TANGO 393 SEQ ID NO: 36.

[0397] In another embodiment, a TANGO 393 family member includes one ormore leucine-rich-repeat domain consensus sequences having an amino acidsequence that is at least about 55%, preferably at least about 65%, morepreferably at least 75%, yet more preferably at least about 85%, andmost preferably at least about 95% identical to amino acids 26 to 57, 58to 81, 82 to 105, 106 to 130, 131 to 154, 155 to 178, 179 to 202, 203 to226, 227 to 250, and/or 260 to 310 of human TANGO 393 of SEQ ID NO: 34,and has at least one TANGO 393 biological activity as described herein.In yet another embodiment, a TANGO 393 family member includes one ormore leucine-rich-repeat domains having an amino acid sequence that isat least about 55%, preferably at least about 65%, more preferably atleast 75%, yet more preferably at least about 85%, and most preferablyat least about 95% identical to amino acid positions 26 to 57, 58 to 81,82 to 105, 106 to 130, 131 to 154, 155 to 178, 179 to 202, 203 to 226,227 to 250, and/or 260 to 310 of mouse TANGO 393 (SEQ ID NO: 36), andhas at least one TANGO 393 biological activity as described herein.

[0398] In one embodiment of a nucleotide sequence of human TANGO 393,the nucleotide at position 5 is adenine (A). In this embodiment, theamino acid at position 2 is lysine (K). In an alternative embodiment, aspecies variant of human TANGO 393 has a nucleotide at position 5 whichis guanine (G). In this embodiment, the amino acid at position 2 isarginine (R), i.e., a conservative substitution.

[0399] In one embodiment of a nucleotide sequence of human TANGO 393,the nucleotide at position 17 is cytosine (C). In this embodiment, theamino acid at position 6 is alanine (A). In an alternative embodiment, aspecies variant of human TANGO 393 has a nucleotide at position 17 whichis thymidine (T). In this embodiment, the amino acid at position 6 isvaline (V), i.e., a conservative substitution.

[0400] In one embodiment of a nucleotide sequence of human TANGO 393,the nucleotide at position 55 is cytosine (C). In this embodiment, theamino acid at position 19 is glutamine (Q). In an alternativeembodiment, a species variant of human TANGO 393 has a nucleotide atposition 55 which is guanine (G). In this embodiment, the amino acid atposition 19 is glutamate (E), i.e., a conservative substitution.

[0401] In one embodiment of a nucleotide sequence of human TANGO 393,the nucleotide at position 118 is adenine (A). In this embodiment, theamino acid at position 40 is threonine (T). In an alternativeembodiment, a species variant of human TANGO 393 has a nucleotide atposition 118 which is thymine (T). In this embodiment, the amino acid atposition 40 is serine (S), i.e., a conservative substitution.

[0402] Human TANGO 393 has LRR from amino acids 26 to 57, 58 to 81, 82to 105, 106 to 130, 131 to 154, 155 to 178, 179 to 202, 203 to 226, 227to 250, and 260 to 310 of SEQ ID NO: 34. These repeats are spaced inbeta-alpha folds in the structure of the protein, so as to create ahydrophobic face that induces particular folding of the protein.

[0403] Human TANGO 393 has five N-glycosylation sites. The first has asequence of NLTI (at amino acids 82-85), the second has a sequence ofNLTH (at amino acids 179 to 182), the third has a sequence of NLSA (atamino acids 237 to 240), the fourth has a sequence of NGSG (at aminoacids 372 to 375), and the fifth has a sequence of NRTR (at amino acids423 to 426). Human TANGO 393 has one Glycosaminoglycan attachment site,the sequence of which is SGGG (at amino acids 436 to 439). Human TANGO393 has one cAMP and cGMP-dependent protein kinase phosphorylation site,the sequence of which is KRAS (at amino acids 2 to 5). Human TANGO 393has five protein kinase C phosphorylation sites, where the first has asequence SQR of (at amino acids 59 to 61), the second has a sequence SFRof (at amino acids 76 to 78), the third has a sequence TFR of (at aminoacids 173 to 175), the fourth has a sequence TGR of (at amino acids 321to 323), and the fifth has a sequence SRK of (at amino acids 420 to422). Human TANGO 393 has five casein kinase II phosphorylation sites,where the first has a sequence of TFRD (at amino acids 173 to 176), thesecond has a sequence of SVPE (at amino acids 192 to 195), the third hasa sequence of SSSE (at amino acids 281 to 284), the fourth has asequence of TDEE (at amino acids 325 to 328), and the fifth has asequence of SVLE (at amino acids 345 to 348). Human TANGO 393 has elevenN-myristylation sites, where the first has the sequence GACVCY (at aminoacids 29 to 34), the second has the sequence GIPAAS (at amino acids 54to 59), and the third has the sequence GNRISH (at amino acids 66 to 71),the fourth has the sequence GLFRGL (at amino acids 148 to 153), and thefifth has the sequence GNRISS (at amino acids 187 to 192), the sixth hasthe sequence GCAVAT (at amino acids 308 to 313), and the seventh has thesequence GLPKCC (at amino acids 331 to 336), the eighth has the sequenceGTLPGS (at amino acids 385 to 390), and the ninth has the sequenceGQAGSG (at amino acids 432 to 437), the tenth has the sequence GGGTGD(at amino acids 438 to 443), and the eleventh has the sequence GALPSL(at amino acids 448 to 453). Human TANGO 393 has a Leucine zipperpattern which has the amino acid sequence LHLDRCGLQELGPGLFRGLAAL (atamino acids 135 to 156).

[0404] Human TANGO 393 maps by homology to ESTs to Chromosome 22 betweenD22S420 and D22S446.

[0405] Clone EpT393, which encodes human TANGO 393, was deposited withthe American Type Culture Collection (10801 University Boulevard,Manassas, Va. 20110-2209) on Jun. 29, 1999 and assigned Accession NumberPTA-295. This deposit will be maintained under the terms of the BudapestTreaty on the International Recognition of the Deposit of Microorganismsfor the Purposes of patent Procedure. This deposit was made merely as aconvenience for those of skill in the art and is not an admission that adeposit is required under 35 U.S.C. §112.

[0406] Mouse TANGO 393

[0407] A cDNA encoding mouse TANGO 393 was identified in an analysis ofa fetal hypothalamus library for screening encoding signal peptides.This analysis led to the identification of a clone, jtmoa038d08,encoding mouse TANGO 393. The mouse cDNA of this clone is 1946nucleotides long (FIG. 40; SEQ ID NO: 35). The open reading frame isfrom nucleotides 226 to 1644 of SEQ ID NO: 35, encodes a 473 amino acidmouse TANGO 393 transmembrane protein (FIG. 40; SEQ ID NO: 36).

[0408]FIG. 41 depicts a hydropathy plot of mouse TANGO 393, the detailsof which are described herein. The dashed vertical line separates thesignal sequence (amino acids 1 to 26 of SEQ ID NO: 36) on the left fromthe mature protein (amino acids 27 to 473 of SEQ ID NO: 36) on theright.

[0409] The signal peptide prediction program SIGNALP (Nielsen, et al.(1997) Protein Engineering 10:1-6) predicted that mouse TANGO 393includes an 26 amino acid signal peptide (amino acid 1 to amino acid 26of SEQ ID NO: 36) preceding the mature protein (corresponding to aminoacid 27 to amino acid 473 of SEQ ID NO: 36). The molecular weight ofmouse TANGO 393 without post-translational modifications is 51.0 kDaprior to the cleavage of the signal peptide, 48.1 kDa after cleavage ofthe signal peptide. The presence of a methionine residue at positions229, 240 and 247 indicates that there can be alternative forms of mouseTANGO 393 of 245 amino acids, 234 amino acids, and 227 amino acids ofSEQ ID NO: 36, respectively.

[0410] Mouse TANGO 393 is a transmembrane protein which contains one ormore of the following domains: (1) an extracellular domain; (2) atransmembrane domain; (3) a cytoplasmic domain; and (4) leucine-richrepeat domain. The mouse TANGO 393 protein contains an extracellulardomain at amino acids 27 to 449, a transmembrane domain at amino acidresidues 450 to 467, and a cytoplasmic domain at amino acid residues 468to 473 of SEQ ID NO: 36.

[0411] In another embodiment, mouse TANGO 393 protein contains a signalsequence of about amino acids 1 to 26 of SEQ ID NO: 36. Alternatively,in another embodiment, a mouse TANGO 393 protein contains a cytoplasmicdomain at amino acids 27 to 449, a transmembrane domain at amino acidresidues 450 to 467, and an extracellular domain at amino acid residues468 to 473 of SEQ ID NO: 36.

[0412] In one embodiment of a nucleotide sequence of mouse TANGO 393,the nucleotide at position 5 is adenine (A). In this embodiment, theamino acid at position 2 is lysine (K). In an alternative embodiment, aspecies variant of mouse TANGO 393 has a nucleotide at position 5 whichis guanine (G). In this embodiment, the amino acid at position 2 isarginine (R), i.e., a conservative substitution.

[0413] In one embodiment of a nucleotide sequence of mouse TANGO 393,the nucleotide at position 59 is cytosine (C). In this embodiment, theamino acid at position 20 is alanine (A). In an alternative embodiment,a species variant of mouse TANGO 393 has a nucleotide at position 59which is thymidine (T). In this embodiment, the amino acid at position20 is valine (V), i.e., a conservative substitution.

[0414] In one embodiment of a nucleotide sequence of mouse TANGO 393,the nucleotide at position 118 is adenine (A). In this embodiment, theamino acid at position 40 is threonine (T). In an alternativeembodiment, a species variant of mouse TANGO 393 has a nucleotide atposition 118 which is thymidine (T). In this embodiment, the amino acidat position 40 is serine (S), i.e., a conservative substitution.

[0415] In one embodiment of a nucleotide sequence of mouse TANGO 393,the nucleotide at position 178 is cytosine (C). In this embodiment, theamino acid at position 60 is glutamine (Q). In an alternativeembodiment, a species variant of mouse TANGO 393 has a nucleotide atposition 178 which is guanine (G). In this embodiment, the amino acid atposition 60 is glutamate (E), i.e., a conservative substitution.

[0416] Mouse TANGO 393 has five N-glycosylation sites. The first has asequence of NLTI (at amino acids 82-85), the second has a sequence ofNLTH (at amino acids 179 to 182), the third has a sequence of NLSM (atamino acids 237 to 240), the fourth has a sequence of NGSG (at aminoacids 372 to 375), and the fifth has a sequence of NRTR (at amino acids423 to 426). Mouse TANGO 393 has one Glycosaminoglycan attachment site,the sequence of which is SGTG (at amino acids 439 to 442). Mouse TANGO393 has one cAMP- and cGMP-dependent protein kinase phosphorylationsite, the sequence of which is KRAS (at amino acids 2 to 5). Mouse TANGO393 has four protein kinase C phosphorylation sites, where the first hasa sequence SQR of (at amino acids 59 to 61), the second has a sequenceSCR of (at amino acids 79 to 81), the third has a sequence TFR of (atamino acids 173 to 175), and the fourth has a sequence SRK of (at aminoacids 420 to 422). Mouse TANGO 393 has eight casein kinase IIphosphorylation sites, where the first has a sequence of TLLE (at aminoacids 105 to 108), the second has a sequence of TFRD (at amino acids 173to 176), the third has a sequence of SVPE (at amino acids 192 to 195),the fourth has a sequence of SSSE (at amino acids 281 to 284), the fifthhas a sequence of SDLE (at amino acids 304 to 307), the sixth has asequence of TDEE (at amino acids 325 to 328), the seventh has a sequenceof SVLE (at amino acids 345 to 348), and the eighth has a sequence ofSSAE (at amino acids 389 to 392). Mouse TANGO 393 has tenN-myristylation sites, where the first has the sequence GACVCY (at aminoacids 29 to 34), the second has the sequence GIPAAS (at amino acids 54to 59), and the third has the sequence GNRISH (at amino acids 66 to 71),the fourth has the sequence GLFRGL (at amino acids 148 to 153), and thefifth has the sequence GCAVAS (at amino acids 308 to 313), the sixth hasthe sequence GTLPSS (at amino acids 385 to 390), and the seventh has thesequence GLPTTG (at amino acids 407 to 412), the eighth has the sequenceGQAGSG (at amino acids 432 to 437), and the ninth has the sequenceGTGDAE (at amino acids 440 to 445), and the tenth has the sequenceGALPAL (at amino acids 448 to 453). Mouse TANGO 393 has a prokaryoticmembrane lipoprotein lipid attachment site with the sequence ofSHVPAASFQSC (at amino acids 70 to 80). Mouse TANGO 393 has a Leucinezipper pattern which has the amino acid sequence LHLDRCGLRELGPGLFRGLAAL(at amino acids 135 to 156).

[0417] Mouse TANGO 393 has LRR from amino acids 26 to 57, 58 to 81, 82to 105, 106 to 130, 131 to 154, 155 to 178, 179 to 202, 203 to 226, 227to 250, and 260 to 310 of SEQ ID NO: 36. These repeats are spaced inbeta-alpha folds in the structure of the protein, so as to create ahydrophobic face that induces particular folding of the protein.

[0418]FIG. 42 depicts an alignment of the open reading frames of humanTANGO 393 and mouse TANGO 393 (SEQ ID NO: 35) demonstrating an identityof 82.8%. The algorithm used to align the sequences was the ALIGNprogram which calculates a global alignment of two sequences. (Version2.0u, Myers and Miller, 1989)

[0419]FIG. 43 depicts an alignment of the immature proteins of humanTANGO 393 (SEQ ID NO: 34) and mouse TANGO 393 (SEQ ID NO: 36)demonstrating an identity of 89.2%. The algorithm used to align thesequences was the ALIGN program which calculates a global alignment oftwo sequences. (Version 2.0u, Myers and Miller, 1989)

[0420] Uses of TANGO 393 Nucleic Acids, Polypeptides and ModulatorsThereof

[0421] As both mouse and human TANGO 393 clones were originallyidentified in a fetal hypothalamus library, TANGO 393 nucleic acids,proteins, and modulators thereof can be used to diagnose disordersand/or modulate the proliferation, differentiation, and/or function ofendocrine cells, in particular hypothalamus, cells. TANGO 393 nucleicacids, proteins and modulators thereof can be utilized to modulateprocesses involved in hypothalamus development, differentiation andactivity, including, but not limited to development, and differentiationand activation of hypothalamus tissues and cells as well as any functionassociated with such cells, and amelioration of one or more symptomsassociated with abnormal function of such cell types. Such disorders caninclude, but are not limited to, malignant or benign hypothalamus cellgrowth.

[0422] Furthermore, as the hypothalamus is the master regulator of theentire endocrine system, as such, TANGO 393 nucleic acids, proteins andmodulators thereof can be used as a therapeutic agent to treat mammalswith abnormal hypothalamic function wherein the mammal exhibits abnormalwhole animal homeostasis, appetite-related disorders, obesity, cachexia,food intake disorders, stress responsiveness disorders, adrenal functiondisorders, pituitary disorders and adrenal disorders. Further, TANGO 393proteins, nucleic acids, or modulators thereof, can be used to treatdisorders of the adrenal cortex, such as hypoadrenalism (e.g., primarychronic or acute adrenocortical insufficiency, and secondaryadrenocortical insufficiency), hyperadrenalism (Cushing's syndrome,primary hyper-aldosteronism, adrenal virilism, and adrenal hyperplasia),or neoplasia (e.g., adrenal adenoma and cortical carcinoma). In anotherexample, TANGO 393 polypeptides, nucleic acids, or modulators thereof,can be used to treat disorders of the thyroid gland, which is partiallyregulated by the hypothalamus, such as hyperthyroidism (e.g., diffusetoxic hyperplasia, toxic multinodular goiter, toxic adenoma, and acuteor subacute thyroiditis), hypothyroidism (e.g., cretinism and myxedema),thyroiditis (e.g., Hashimoto's thyroiditis, subacute granulomatousthyroiditis, subacute lymphocytic thyroiditis, Riedel's thryroiditis),Graves' disease, goiter (e.g., simple diffuse goiter and multinodulargoiter), or tumors (e.g., adenoma, papillary carcinoma, follicularcarcinoma, medullary carcinoma, undifferentiated malignant carcinoma,Hodgkin's disease, and non-Hodgkin's lymphoma).

[0423] TANGO 393 exhibits homology to genes which contain sequencesreferred to as Leucine Rich Repeats (LRR), for example, SLIT-1,leucine-rich α-2-Glycoprotein and Platelet Glycoprotein V precursor. Assuch, TANGO 393 nucleic acids, proteins and modulators thereof can beused to treat subjects with defects in leucine-rich-repeat genes shownto cause various diseases, including but not limited to Bernard-Soulierdisease, a bleeding disorder. Further, as TANGO 393 has homology toPlatelet Glycoprotein V (GPV) precursor, TANGO 393 nucleic acids,proteins and modulators thereof can be used to diagnose disorders and/ormodulate platelet activity, thrombin activity, von Willebrand Factorassembly and activation, or ADP/epinephrine-, cathepsin G-, andTRAP-induced decrease in platelet surface GPV expression.

[0424] Furthermore, TANGO 393 proteins, nucleic acids and modulatorsthereof can be used to modulate the pathogenesis of infectious diseases,for example, diseases that are affected by the expression ofleucine-rich-repeat proteins such as the type-1 human immunodeficiencyvirus (HIV-1) Rev protein, which is the trans-activating region of thevirus (Kobe and Deisenhofer, 1994, TIBS, 19:415-421).

[0425] LRR containing proteins are tissue organizers, wherein theyorient and order collagen fibrils during ontogeny and are involved inpathological processes such as wound healing, tissue repair, and tumorstroma formation. These properties are rooted in their bifunctionalcharacter: the protein moiety binding collagen fibrils at strategicloci, the microscopic gaps between staggered fibrils, and the highlycharged glycosaminoglycans extending out to regulate interfibrillardistances and thereby establishing the exact topology of fibrillarcollagens in tissues. Therefore, TANGO 393 nucleic acids, proteins andmodulators thereof can be used to disrupt intercellular andintracellular protein interactions or cellular signaling in tissues orcells, for example in the hypothalamus. More particularly, the TANGO 393nucleic acids, proteins and modulators thereof can be used to modulatewound healing (e.g., platelet activation), tissue repair and tumorstroma formation as well. Furthermore, TANGO 393 nucleic acids, proteinsand modulators thereof can be used to diagnose disorders and/or modulatethe function of the hypothalamus as it relates to control of endocrinefunction, regulation of whole animal homeostasis and modulation ofdiurnal requirements, appetite as related to obesity or cachexia, andgenerally weight control in mammals.

[0426] Proteins with LRR also interact with soluble growth factors,modulate their functional activity, and bind to cell surface receptors.The latter interaction affects cell cycle progression in a variety ofcellular systems and could explain changes in the expression of thesegene products around the invasive neoplastic cells and in regeneratingtissues. See Generally, Iozzo, 1997, Crit. Rev. Biochem. Mol. Biol.,32(2):141-74. As such, TANGO 393 nucleic acids, proteins and modulatorsthereof can be used to modulate disorders associated with aberrantexpression of TANGO 393 in cancerous (e.g., tumor) cells that do notnormally express TANGO 393. Such disorders can include, for example,ones associated with tumor cell migration and progression to metastasis.

[0427] As TANGO 393 exhibits homology to the SLIT-1 proteins, TANGO 393proteins, nucleic acids and modulators thereof may participate in theformation and maintenance of the nervous and endocrine systems by e.g.,protein-protein interactions. Northern blot analysis has revealed thatthe human SLIT-1, -2, and -3 mRNAs are exclusively expressed in thebrain, spinal cord, and thyroid, respectively. In situ hybridizationstudies indicated that the rat SLIT-1 mRNA is specifically expressed inthe neurons of fetal and adult forebrains (Itoh et al., Brain Res MolBrain Res 1998 Nov 20;62(2):175-86.) This suggests a role for TANGO 393nucleic acids, proteins and modulators thereof in brain development andneural function. Therefore, the TANGO 393 nucleic acids, proteins andmodulators thereof may be useful to disrupt protein interaction orcellular signaling in brain tissues or cells. In particular, TANGO 393protein, nucleic acids and modulators thereof could be useful to treatneural related disorders or neural damage, such as for regenerativeneural repair after damage by trauma, degeneration, or inflammatione.g., multiple sclerosis, spinal cord injuries, infarction, infection,malignancy, exposure to toxic agents, nutritional deficiency,paraneoplastic syndromes, and degenerative nerve diseases including butnot limited to Alzheimer's disease, Parkinson's disease, Huntington'sChorea, amyotrophic lateral sclerosis, progressive supra-nuclear palsy,and other dementia.

[0428] TANGO 393 expression can be utilized as a marker (e.g., an insitu marker) for specific tissues (e.g., the hypothalamus) and/or cells(e.g., hypothalamic cells) in which TANGO 393 is expressed. TANGO 393nucleic acids can also be utilized for chromosomal mapping, or aschromosomal markers, e.g., in radiation hybrid mapping.

[0429] Human TANGO 402

[0430] A cDNA encoding human TANGO 402 was identified by analyzing thesequences of clones present in a human 9 week fetus library forsequences that encode wholly secreted or transmembrane proteins. Thisanalysis led to the identification of a clone, jthga055h07, encodinghuman TANGO 402. The human TANGO 402 cDNA of this clone is 1348nucleotides long (FIG. 44; SEQ ID NO: 37). The open reading frame ofthis cDNA, nucleotides 87 to 707 of SEQ ID NO: 37, encodes a 207 aminoacid transmembrane protein (FIG. 44; SEQ ID NO: 38).

[0431]FIG. 45 depicts a hydropathy plot of human TANGO 402, the detailsof which are described herein.

[0432] The signal peptide prediction program SIGNALP (Nielsen et al.,1997, Protein Engineering 10: 1-6) predicted that human TANGO 402includes a 50 amino acid signal peptide (amino acid 1 to amino acid 50of SEQ ID NO: 38) preceding the mature human TANGO 402 protein(corresponding to amino acid 51 to amino acid 207 of SEQ ID NO: 38). Themolecular weight of human TANGO 402 protein without post-translationalmodifications is 24.0 kDa prior to the cleavage of the signal peptide,18.1 kDa after cleavage of the signal peptide.

[0433] Human TANGO 402 protein is a transmembrane protein that containsan extracellular domain at amino acids 1 to 133 or a matureextracellular domain at amino acid residues 51 to 133, a transmembranedomain at amino acid residues 134 to 151, and a cytoplasmic domain atamino acid residues 152 to 207 of SEQ ID NO: 38.

[0434] Alternatively, in another embodiment, a human TANGO 402 proteincontains a cytoplasmic domain at amino acids 1 to 133 or a maturecytoplasmic domain at amino acid residues 51 to 133, a transmembranedomain at amino acid residues 134 to 151, and an extracellular domain atamino acid residues 152 to 207 of SEQ ID NO: 38. In another embodiment,a TANGO 402 protein contains a signal sequence of about amino acids 1 to50 of SEQ ID NO: 38. The signal sequence is usually cleaved duringprocessing of the mature protein. In the case of, e.g., transmembrane4-type proteins, the signal peptide is generally not cleaved, butbecomes a transmembrane-anchoring domain of the polypeptide.

[0435] A TANGO 402 family member can include of one or more of thefollowing domains: (1) an extracellular domain; (2) a transmembranedomain; and (3) a cytoplasmic domain. In one embodiment, a TANGO 402protein contains an extracellular domain at amino acids 1 to about 133or a mature extracellular domain at about amino acid residues 51 to 133,a transmembrane domain at about amino acid residues 134 to 151, and acytoplasmic domain at about amino acid residues 152 to 207 of SEQ ID NO:38.

[0436] A TANGO 402 family member can include a signal sequence. Incertain embodiments, a TANGO 402 family member has the amino acidsequence of SEQ ID NO: 38, and the signal sequence is located at aminoacids 1 to 48, 1 to 49, 1 to 50, 1 to 51 or 1 to 52. In such embodimentsof the invention, the extracellular domain and the mature proteinresulting from cleavage of such signal peptides are also includedherein. For example, the cleavage of a signal sequence consisting ofamino acids 1 to 48 results in an extracellular domain consisting ofamino acids 49 to 133 and the mature TANGO 402 protein corresponding toamino 49 to 207 of SEQ ID NO: 38.

[0437] A TANGO 402 family member can include a C-type lectin domain or aC-type lectin-like domain.

[0438] A C-type lectin domain typically has the following consensussequence:C-[LIVMFATG]-x(5,12)-[WL]-x-[DNSR]-x(2)-C-x(5,6)-[FYWLIVSTA]-[LIVSTA]-C,wherein C is a cysteine residue, [LIVMFATG] is a leucine, isoleucine,methionine, phenylalanine, alanine, threonine or glycine residue, x isany amino acid and the number in parentheses indicates the number ofamino acids, [WL] is either a tryptophan or leucine residue, [DNSR] is aaspartic acid, asparagine, serine or arginine residue, [FYWLIVSTA] is aphenylalanine, tyrosine, tryptophan, leucine, isoleucine, valine,serine, threonine or alanine residue, and [LIVSTA] is a leucine,isoleucine, valine, serine, threonine or alanine residue. C-type lectindomains contain four cysteines, which are involved in two disulfidebonds, and are about 110 to 130 amino acid residues. C-type lectindomains typically function as calcium-dependent carbohydrate-recognitiondomains and have been found in various proteins including, but notlimited to, asialoglycoprotein receptors (ASGPR), pulmonarysurfactant-associated protein A (SP-A), mannan-binding proteins,L-selectin, neurocan, and tetranectin. These proteins have variousfunctions including, for example, cell adhesion (i.e., L-selectin).ASGPR mediates the endocytosis of plasma glycoprotein to which theterminal salic acid-residue in their carbohydrated moieties has beenremoved. SP-A binds to surfactant phospholipids and contributes to lowerthe surface tension at the air-liquid interface in the alveoli of thelung.

[0439] A C-type lectin-like domain as described herein has the followingconsensus sequence:C-[LIVMFATG]-x-(5,12)-[DNSR]-x(2)-C-x(5,6)-[LIVSTA]-C, wherein C is acysteine residue, [LIVMFATG] is a leucine, isoleucine, methionine,phenylalanine, alanine, threonine or glycine residue, “x” is any aminoacid and the number in parentheses indicates the number of amino acids[DNSR] is an aspartic acid, asparagine, serine or arginine residue, and[LIVSTA] is a leucine, isoleucine, valine, serine, threonine or alanineresidue. In one embodiment, a TANGO 402 family member has the amino acidsequence of SEQ ID NO: 38 and, preferably, a C-type lectin-like domainis located at about amino acid positions 104 to 193, wherein theconsensus sequence is at about amino acid positions 172 to 193 of SEQ IDNO: 38.

[0440] In another embodiment, a TANGO 402 family member includes one ormore C-type lectin-like domains having an amino acid sequence that is atleast about 55%, preferably at least about 65%, more preferably at least75%, yet more preferably at least about 85%, and most preferably atleast about 95% identical to amino acids 104 to 193 of SEQ ID NO: 38.

[0441] In another embodiment, a TANGO 402 family member includes one ormore C-type lectin-like domains having an amino acid sequence that is atleast about 55%, preferably at least about 65%, more preferably at least75%, yet more preferably at least about 85%, and most preferably atleast about 95% identical to amino acids 104 to 193 of SEQ ID NO: 38,and has at least one TANGO 402 biological activity as described herein.

[0442] In another embodiment, a TANGO 402 family member includes one ormore C-type lectin-like domains having an amino acid sequence that is atleast about 55%, preferably at least about 65%, more preferably at least75%, yet more preferably at least about 85%, and most preferably atleast about 95% identical to amino acids 104 to 193 of SEQ ID NO: 38 andincludes a cysteine residue N-terminal to the consensus sequence. In yetanother embodiment, a TANGO 402 family member includes one or moreC-type lectin-like domain having an amino acid sequence that is at leastabout 55%, preferably at least about 65%, more preferably at least 75%,yet more preferably at least about 85%, and most preferably at leastabout 95% identical to amino acids 104 to 193 of SEQ ID NO: 38, includesa cysteine residue N-terminal to the consensus sequence, and has atleast one TANGO 402 biological activity as described herein.

[0443] In another embodiment, the C-type lectin-like domain of TANGO 402is a C-type lectin domain, which has the following consensus sequence:C-[LIVMFATG]-x(5,12)-[WL]-x-[DNSR]-x(2)-C-x(5,6)-[FYWLIVSTA]-[LIVSTA]-C,wherein C is a cysteine residue, [LIVMFATG] is a leucine, isoleucine,methionine, phenylalanine, alanine, threonine or glycine residue, x isany amino acid, [WL] is either a tryptophan or leucine residue, [DNSR]is a aspartic acid, asparagine, serine or arginine residue, [FYWLIVSTA]is a phenylalanine, tyrosine, tryptophan, leucine, isoleucine, valine,serine, threonine or alanine residue, and [LIVSTA] is a leucine,isoleucine, valine, serine, threonine or alanine residue. In thisembodiment, a TANGO 402 family member includes one or more C-typelectin-like domains having an amino acid sequence that is at least about55%, preferably at least about 65%, more preferably at least 75%, yetmore preferably at least about 85%, and most preferably at least about95% identical to amino acids 104 to 193 of SEQ ID NO: 38.

[0444] In one embodiment of a nucleotide sequence of human TANGO 402,the nucleotide at position 28 is cytosine (C). In this embodiment, theamino acid at position 10 is leucine (L). In an alternative embodiment,a species variant of human TANGO 402 has a nucleotide at position 28which is guanine (G). In this embodiment, the amino acid at position 10is valine (V), i.e., a conservative substitution.

[0445] In one embodiment of a nucleotide sequence of human TANGO 402,the nucleotide at position 58 is cytosine (C). In this embodiment, theamino acid at position 20 is glutamine (A). In an alternativeembodiment, a species variant of human TANGO 402 has a nucleotide atposition 58 which is guanine (G). In this embodiment, the amino acid atposition 20 is glutamate (E), i.e., a conservative substitution.

[0446] In one embodiment of a nucleotide sequence of human TANGO 402,the nucleotide at position 61 is adenine (A). In this embodiment, theamino acid at position 21 is lysine (K). In an alternative embodiment, aspecies variant of human TANGO 402 has a nucleotide at position 61 whichis guanine (G). In this embodiment, the amino acid at position 21 isarginine (R), i.e., a conservative substitution.

[0447] In one embodiment of a nucleotide sequence of human TANGO 402,the nucleotide at position 64 is thymine (T). In this embodiment, theamino acid at position 22 is serine (S). In an alternative embodiment, aspecies variant of human TANGO 402 has a nucleotide at position 64 whichis adenine (A). In this embodiment, the amino acid at position 22 isthreonine (T), i.e., a conservative substitution.

[0448] Two N-glycosylation sites are present in human TANGO 402. Thefirst has the sequence NISS (at amino acid residues 67 to 70) and thesecond has the sequence NGTS (at amino acid residues 202 to 205). Sixprotein kinase C phosphorylation sites are present in human TANGO 402.The first has the sequence SFK (at amino acid residues 11 to 13), thesecond has the sequence SFK (at amino acid residues 95 to 97), the thirdhas the sequence TWK (at amino acid residues 98 to 100), the fourth hasthe sequence SQR (at amino acid residues 102 to 104), the fifth has thesequence SLK (at amino acid residues 128 to 130), and the sixth has thesequence TFK (at amino acid residues 188 to 190). Three casein kinase IIphosphorylation sites are present in human TANGO 402. The first has thesequence TGID (at amino acid residues 49 to 52), the second has thesequence TWKE (at amino acid residues 98 to 101), and the third has thesequence SQRD (at amino acid residues 102 to 105). Human TANGO 402 has atyrosine kinase phosphorylation site having the sequence KSKDFSLY atamino acid residues 21 to 28). Human TANGO 402 has an N-myristylationsite having the sequence GLYVTF at amino acid residues 138 to 143.

[0449] Human TANGO 402 includes a C-type lectin (CTL)-like domain atamino acid residues 104 to 193 of SEQ ID NO: 38. CTL domains have beenshown to function as a calcium-dependent carbohydrate-recognitiondomain.

[0450] Human TANGO 402 is homologous to human lectin-like oxidized LDLreceptor 1 (LOX-1), which is the receptor for oxidized lipoprotein(Sawamura et al., 1997, Science, 386:73-77). LOX-1 is involved inoxidized low-density lipoprotein (Ox-LDL) uptake and subsequent foamcell transformation in macrophages and smooth muscle cells in theatherosclerotic intima (Kume et al., 1998, Cir. Res., 83:322-327;Yamada, et al., 1998, Cell. Mol. Life Sci., 54(7):628-640; Moriwaki etal., 1998, Artherioscler. Thromb. Vasc. Biol., 18(10):1541-1547; Napaseet al., 1998, J. Biol. Chem., 273(50):33702-33707).

[0451]FIG. 46 depicts an alignment of the human TANGO 402 amino acidsequence (SEQ ID NO: 38) with the human LOX-1 amino acid sequence (SEQID NO: 47; Accession Number AB010710). As shown in the figure, the aminoacid sequence of LOX-1 is 25.1% identical to the amino acid sequence ofhuman TANGO 402 (SEQ ID NO: 38).

[0452]FIG. 47 depicts an alignment of the open reading frames of humanTANGO 402 and LOX-1 (SEQ ID NO: 47), which are 42.0% identical. Theoverall nucleic acid sequence identity between human TANGO 402 (SEQ IDNO: 37) and LOX-1 (SEQ ID NO: 47) is 44.0%.

[0453] Clone EpT402, which encodes human TANGO 402, was deposited withthe American Type Culture Collection (10801 University Boulevard,Manassas, Va. 20110-2209) on Jun. 29, 1999 and assigned Accession NumberPTA-294. This deposit will be maintained under the terms of the BudapestTreaty on the International Recognition of the Deposit of Microorganismsfor the Purposes of patent Procedure. This deposit was made merely as aconvenience for those of skill in the art and is not an admission that adeposit is required under 35 U.S.C. §112.

[0454] Uses of TANGO 402 Nucleic Acids. Polypeptides. and ModulatorsThereof

[0455] As TANGO 402 was originally found in a human fetal library, TANGO402 nucleic acids, proteins, and modulators thereof can be used todiagnose disorders associated with cells, tissues, and/or organs in theembryo or fetus, or modulate the proliferation, development,differentiation, and/or function of cells, tissues, and/or organs in theembryo or fetus.

[0456] In addition, as TANGO 402 is homologous to LOX-1, TANGO 402nucleic acids, proteins and modulators thereof can be utilized todiagnose disorders, modulate development, differentiation, proliferationand/or activity of immune cells, such as macrophages and endothelialcells, e.g., the phagocytosis of aged/apoptotic cells by endothelialcells. TANGO 402 nucleic acids, proteins and modulators thereof can beutilized to treat, inhibit and/or prevent disorders and diseasesassociated with the aberrant activity of the cells, tissues or organs inwhich TANGO 402 is expressed, e.g. endothelial activity. TANGO 402nucleic acids, proteins and modulations thereof can also be used todiagnose disorders and/or modulate symptoms associated withatherosclerosis (e.g., atherosclerotic cardiovascular disease) andAlzheimer's disease. TANGO 402 nucleic acids, proteins and modulatorsthereof can be used to diagnose disorders associated with host immunedefenses and/or modulate host immune defenses, e.g., modulating theactivation of macrophages. TANGO 402 nucleic acids, proteins andmodulators thereof can be utilized to treat and/or prevent obesity,diabetes, and inflammatory disorders (e.g., asthma, arthritis, multiplesclerosis, allergies, hepatitis and infections).

[0457] TANGO 402 nucleic acids, proteins and modulators thereof can beused to modulate e.g., (1) the ability to modulate, e.g., prevent, lipiddeposition, e.g., in arteries, and thus modulate, e.g., prevent, intimalthickening; (2) the ability to modulate, e.g., induce or prevent,changes in cells, e.g., transformation of cells (e.g., macrophages andsmooth muscle cells) into foam cells and functional alteration of cells(e.g., endothelial cells, e.g., intimal neovascular endothelial cells);(3) the ability to bind and phagocytose cells, e.g., aged and apoptoticcells; and (4) the ability to remove debris, e.g., apoptotic cells, fromblood vessel walls.

[0458] In another example, TANGO 402 nucleic acids, proteins andmodulators thereof can be used to modulate e.g., (1) the ability tomodulate homeostasis, e.g., vascular homeostasis, e.g., by modulating,e.g., preventing the impairment of, nitric oxide production; (2) theability to modulate, e.g., inhibit, the expression of molecules, e.g.,adhesion molecules (e.g., leukocyte adhesion molecules) and growthfactors (e.g., smooth-muscle growth factors); (3) the ability to alter,e.g., increase, expression in response to stimuli, e.g., TNF, shearstress, and pathophysiological stimuli relevant to disorders (e.g.,atherosclerosis and inflammation).

[0459] In yet another example, TANGO 402 nucleic acids, proteins andmodulators thereof can be used to modulate e.g., (1) the ability toform, e.g., stabilize, promote, facilitate, inhibit, or disrupt,cell-extracellular matrix interactions, e.g., adhesion between cells andextracellular matrix; (2) the ability to form, e.g., stabilize, promote,facilitate, inhibit, or disrupt, cell to cell and cell to blood productinteraction, e.g., between leukocytes and platelets or leukocytes andvascular endothelial cells; and (3) the ability to recognize largemolecules, e.g., carbohydrates.

[0460] In light of the fact that TANGO 402 is homologous to LOX-1, TANGO402 nucleic acids, proteins and modulators thereof have biologicalactivities that can also include the ability to perform one or more ofthe functions of LOX-1 described, for example, in the following:Sawamura et al. (1997) Nature. 386:73-77; Kataoka et al. (1999)Circulation. 99:3110-3117; and Kita (1999) Circulation Research.84:1113-1115, the contents of each of which is incorporated herein byreference in its entirety.

[0461] Moreover, due to TANGO 402's homology to LOX-1, as evidenced bythe presence of similar domains and mapping coordinates between the twomolecules, TANGO 402 nucleic acids, proteins and modulators thereof canbe used to modulate or treat disorders in which LOX-1 plays a role, someof which are described in the following references: Sawamura et al.(1997) Nature. 386:73-77; Kataoka et al. (1999) Circulation.99:3110-3117; and Kita (1999) Circulation Research. 84:1113-1115, thecontents of each of which is incorporated herein by reference in itsentirety.

[0462] Furthermore, TANGO 402 nucleic acids, proteins and modulatorsthereof can modulate or treat atherosclerosis, e.g., by binding tooxidatively modified low density lipoprotein (Ox-LDL) and its lipidconstituents, thus preventing lipid deposition and intimal thickening inthe arteries, and thus preventing the induction of endothelialexpression of leukocyte adhesion molecules and smooth-muscle growthfactors (both which are implicated in atherogenesis).

[0463] In another example, TANGO 402 nucleic acids, proteins andmodulators thereof modulate or treat immune related diseases anddisorders. As LOX-1 is implicated in inflammation, and as LOX-1 hashighest homology with the NKR-P1 family of proteins, which are involvedin target-cell recognition and natural killer cell activation, TANGO 402nucleic acids, proteins and modulators thereof can be used to diagnosedisorders and/or modulate or treat inflammatory disorders such asbacterial infection, psoriasis, septicemia, cerebral malaria,inflammatory bowel disease, multiple sclerosis, arthritis (e.g.,rheumatoid arthritis, osteoarthritis), and allergic inflammatorydisorders (e.g., asthma, psoriasis), and processes. Further, TANGO 402nucleic acids, proteins and modulators thereof can be used to identify,diagnose and/or modulate or treat immune disorders including, e.g.,autoimmune disorders (e.g., arthritis, graft rejection (e.g., allograftrejection), and T cell autoimmune disorders (e.g., AIDS)) andinflammatory disorders.

[0464] TANGO 402 nucleic acids, proteins and modulators thereof be usedto identify, diagnose and/or modulate or treat TNF-related disorders, asLOX-1 expression is induced by tumor necrosis factors. Such disordersinclude, e.g., acute myocarditis, myocardial infarction, congestiveheart failure, T cell disorders (e.g., dermatitis, fibrosis)),differentiative and apoptotic disorders, and disorders related toangiogenesis (e.g., tumor formation and/or metastasis, cancer). As LOX-1expression is upregulated in hypertensive rats, and as LOX-I levels aredownregulated in patients treated with ACE (angiotensin convertingenzyme) inhibitors, TANGO 402 can also play a role in treatinghypertension and congestive heart failure.

[0465] As both TANGO 402 has C-type lectin domains or C-type lectin-likedomains, and is similar in that respect to the selecting, which areimplicated in cell-cell recognition (including endothelial-leukocyteadhesion), TANGO 402 nucleic acids, proteins and modulators thereof canbe used to identify, diagnose and/or modulate or treat cell adhesion orcell migration/motility related disorders. Such disorders include, e.g.,disorders associated with adhesion and migration of cells, e.g.,platelet aggregation disorders (e.g., Glanzmann's thromboasthemia, whichis a bleeding disorders characterized by failure of platelet aggregationin response to cell stimuli), inflammatory disorders (e.g., leukocyteadhesion deficiency, which is a disorder associated with impairedmigration of neutrophils to sites of extravascular inflammation),disorders associated with abnormal tissue migration during embryodevelopment, and tumor metastasis.

[0466] As TANGO 402 has a C-type lectin domain or C-type lectin-likedomain, TANGO 402 nucleic acids, proteins and modulators thereof can beused to diagnose C-type lectin disorders and/or modulatecalcium-dependent carbohydrate recognition. TANGO 402 proteins exhibithomology to lectins. In light of this, TANGO 402 nucleic acids, proteinsand modulators thereof can be utilized to modulate cell-cell,cell-extracellular matrix (ECM) interactions, cell adhesion, cellmigration and cell signaling. TANGO 402 nucleic acids, proteins andmodulators thereof can be utilized to treat and/or prevent disorders anddiseases associated with aberrant cell-cell, cell-ECM interactions, cellmigration, cell adhesion and cell-signaling, as well as treating andpreventing tumor cell metastasis. TANGO 402 nucleic acids, proteins andmodulators thereof can also be utilized to treat and/or prevent themigration of cancerous and precancerous cells (e.g., tumor migration).

[0467] TANGO 402 nucleic acids, proteins and modulators thereof can alsobe used to modulate cell proliferation, e.g., abnormal cellproliferation. Such modulation may, for example, be via modulation ofone or more elements involved in signal transduction cascades.

[0468] TANGO 402 expression can be utilized as a marker (e.g., an insitu marker) for specific tissues (e.g., fetal tissues) and/or cells(e.g., fetal cells) in which TANGO 402 is expressed. TANGO 402 nucleicacids can also be utilized for chromosomal mapping, or as chromosomalmarkers, e.g., in radiation hybrid mapping.

[0469] Human TANGO 351

[0470] A cDNA encoding human TANGO 351 was identified by analyzing thesequences of clones present in a human fetal kidney library forsequences that encode wholly secreted or transmembrane proteins. Thisanalysis led to the identification of a clone, jthKa90d12, encodinghuman TANGO 351. The human TANGO 351 cDNA of this clone is 3345nucleotides long (FIG. 48; SEQ ID NO: 39). The open reading frame ofthis cDNA, nucleotides 143 to 1588 of SEQ ID NO: 39, encodes a 482 aminoacid transmembrane protein (FIG. 48; SEQ ID NO: 40).

[0471]FIG. 49 depicts a hydropathy plot of human TANGO 351, the detailsof which are described herein.

[0472] The signal peptide prediction program SIGNALP (Nielsen et al.,1997, Protein Engineering 10:1-6) predicted that human TANGO 351includes a 24 amino acid signal peptide (amino acid 1 to amino acid 24of SEQ ID NO: 40) preceding the mature TANGO 351 protein (correspondingto amino acid 25 to amino acid 482 of SEQ ID NO: 40). In instanceswherein the signal peptide is cleaved, the molecular weight of TANGO 351protein without post-translational modifications is 53.4 kDa prior tothe cleavage of the signal peptide, and 51.1 kDa after cleavage of thesignal peptide.

[0473] Human TANGO 351 protein is a transmembrane protein that containsan extracellular domain at amino acid residues 25 to 458, atransmembrane domain at amino acid residues 459 to 476, and acytoplasmic domain at amino acid residues 477 to 482 of SEQ ID NO: 40.

[0474] In instances wherein the signal peptide is not cleaved, humanTANGO 351 has extracellular domains at amino acid residues contains anextracellular domain at amino acid residues 1 to 458, a transmembranedomain at amino acid residues 459 to 476, and a cytoplasmic domain atamino acid residues 477 to 482 of SEQ ID NO: 40. In this embodiment, themature TANGO 351 protein corresponds to amino acids 25 to 482 of SEQ IDNO: 40.

[0475] In certain embodiments, a TANGO 351 family member has the aminoacid sequence of SEQ ID NO: 40, and the signal sequence is located atamino acids 1 to 22, 1 to 23, 1 to 24, 1 to 25 or 1 to 26. In suchembodiments of the invention, the domains and the mature proteinresulting from cleavage of such signal peptides are also includedherein. For example, the cleavage of a signal sequence consisting ofamino acids 1 to 24 results in an extracellular domain consisting ofamino acids 25 to 458 of SEQ ID NO: 40 and the mature TANGO 351 proteincorresponding to amino acids 25 to 482 of SEQ ID NO: 40.

[0476] Alternatively, in another embodiment, a human TANGO 351 proteincontains a cytoplasmic domain at amino acid residues 25 to 458, atransmembrane domain at amino acid residues 459 to 476, and anextracellular domain at amino acid residues 477 to 482 of SEQ ID NO: 40.

[0477] In one embodiment a cDNA sequence of human TANGO 351 has anucleotide at position 153 which is cytosine (C). In this embodiment,the eDNA contains an open reading frame encoding a polypeptide having anamino acid at position 4 that is alanine (A). In an alternativeembodiment, a species variant cDNA sequence of human TANGO 351 has anucleotide at position 153 which is thymine (T). In this embodiment, thecDNA contains an open reading frame encoding a polypeptide having anamino acid at position 4 that is valine (V), i.e., a conservativesubstitution.

[0478] In another embodiment a cDNA sequence of human TANGO 351 has anucleotide at position 165 which is adenine (A). In this embodiment, thecDNA contains an open reading frame encoding a polypeptide having anamino acid at position 8 that is tyrosine (Y). In an alternativeembodiment, a species variant cDNA sequence of human TANGO 351 has anucleotide at position 165 which is thymine (T). In this embodiment, thecDNA contains an open reading frame encoding a polypeptide having anamino acid at position 8 that is phenylalanine (F), i.e., a conservativesubstitution.

[0479] In another embodiment a cDNA sequence of human TANGO 351 has anucleotide at position 269 which is guanine (G). In this embodiment, thecDNA contains an open reading frame encoding a polypeptide having anamino acid at position 43 that is aspartate (D). In an alternativeembodiment, a species variant cDNA sequence of human TANGO 351 has anucleotide at position 269 which is adenine (A). In this embodiment, thecDNA contains an open reading frame encoding a polypeptide having anamino acid at position 43 that is asparagine (N), i.e., a conservativesubstitution.

[0480] In another embodiment a cDNA sequence of human TANGO 351 has anucleotide at position 273 which is guanine (G). In this embodiment, thecDNA contains an open reading frame encoding a polypeptide having anamino acid at position 44 that is arginine (R). In an alternativeembodiment, a species variant cDNA sequence of human TANGO 351 has anucleotide at position 273 which is adenine (A). In this embodiment, thecDNA contains an open reading frame encoding a polypeptide having anamino acid at position 44 that is lysine (K), i.e., a conservativesubstitution.

[0481] Two N-glycosylation sites are present in TANGO 351. The first hasthe sequence NQTR (at amino acid residues 131 to 134) and the second hasthe sequence NFSE (at amino acid residues 353 to 356).

[0482] Two cAMP- and cGMP-dependent protein kinase phosphorylation sitesare present in TANGO 351. The first has the sequence RRAS (at amino acidresidues 94 to 97) and the second has the sequence KRPT (at amino acidresidues 424 to 427).

[0483] TANGO 351 has seven protein kinase C phosphorylation sites. Thefirst has the sequence TGR (at amino acid residues 62 to 64), the secondhas the sequence SRR (at amino acid residues 119 to 121), the third hasthe sequence TGR (at amino acid residues 127 to 129), the fourth has thesequence SAR (at amino acid residues 159 to 161), the fifth has thesequence SPR (at amino acid residues 193 to 195), the sixth has thesequence STR (at amino acid residues 323 to 325), and the seventh hasthe sequence TER (at amino acid resides 370 to 372).

[0484] Six casein kinase II phosphorylation sites are present in TANGO351. The first has the sequence TEAD (at amino acid residues 104 to107), the second has the sequence TMHE amino acid residues 173 to 176),the third has the sequence SGCE (at amino acid residues 268 to 271), thefourth has the sequence TPMD (at amino acid residues 342 to 345), thefifth has the sequence TERD (at amino acid residues 370 to 373), and thesixth has the sequence SSPD (at amino acid residues 417 to 420).

[0485] TANGO 351 has three tyrosine kinase phosphorylation sites. Thefirst has the sequence RGATEADY (at amino acid residues 101 to 108), thesecond has the sequence RLVEELY (at amino acid residues 195 to 201), andthe third has the sequence RSWEGYY (at amino acid residues 290 to 296).Four N-myristylation sites are present in TANGO 351. The first has thesequence GATEAD (at amino acid residues 102 to 107), the second has thesequence GTPSTR (at amino acid residues 320 to 325), the third has thesequence GGAGAW (at amino acid residues 361 to 366), and the fourth hasthe sequence GQRPTD (at amino acid residues 410 to 415).

[0486] TANGO 351 has a prokaryotic membrane lipoprotein lipid attachmentsite with the sequence HLGGWWVSSGC (at amino acid residues 260 to 270).

[0487] Clone EpT351, which encodes human TANGO 351, was deposited withthe American Type Culture Collection (10801 University Boulevard,Manassas, Va. 20110-2209) on Jul. 23, 1999 and assigned Accession NumberPTA-424. This deposit will be maintained under the terms of the BudapestTreaty on the International Recognition of the Deposit of Microorganismsfor the Purposes of patent Procedure. This deposit was made merely as aconvenience for those of skill in the art and is not an admission that adeposit is required under 35 U.S.C. §112.

[0488] Uses of TANGO 351 Nucleic Acids, Polypeptides, and ModulatorsThereof

[0489] As TANGO 351 was originally found in a human fetal kidneylibrary, TANGO 351 nucleic acids, proteins and modulators thereof can beused to modulate the proliferation, development, differentiation, and/orfunction of kidney cells and the kidney. TANGO 351 nucleic acids,proteins and modulators thereof can be used to modulate or treat renaldisorders, such as glomerular diseases (e.g., acute and chronicglomerulonephritis, rapidly progressive glomerulonephritis, nephroticsyndrome, focal proliferative glomerulonephritis, glomerular lesionsassociated with systemic disease, such as systemic lupus erythematosus,Goodpasture's syndrome, multiple myeloma, diabetes, neoplasia, sicklecell disease, and chronic inflammatory diseases), tubular diseases(e.g., acute tubular necrosis and acute renal failure, polycystic renaldiseasemedullary sponge kidney, medullary cystic disease, nephrogenicdiabetes, and renal tubular acidosis), tubulointerstitial diseases(e.g., pyelonephritis, drug and toxin induced tubulointerstitialnephritis, hypercalcemic nephropathy, and hypokalemic nephropathy),acute and rapidly progressive renal failure, chronic renal failure,nephrolithiasis, vascular diseases (e.g., hypertension andnephrosclerosis, microangiopathic hemolytic anemia, atheroembolic renaldisease, diffuse cortical necrosis, and renal infarcts), or tumors(e.g., renal cell carcinoma and nephroblastoma).

[0490] In view of the fact that TANGO 351 is expressed in fetal cells,TANGO 351 nucleic acids, proteins and modulators thereof can be used forthe development of an embryo and/or fetus.

[0491] TANGO 351 expression can be utilized as a marker (e.g., an insitu marker) for specific tissues (e.g., the kidney) and/or cells (e.g.,renal cells) in which TANGO 351 is expressed. TANGO 351 nucleic acidscan also be utilized for chromosomal mapping, or as chromosomal markers,e.g., in radiation hybrid mapping.

[0492] Human TANGO 509

[0493] A cDNA encoding human TANGO 509 was identified by analyzing thesequences of clones present in a mammary epithelium library forsequences that encode wholly secreted or transmembrane proteins. Thisanalysis led to the identification of a clone, jthvb017h11, encodinghuman TANGO 509. The human TANGO 509 cDNA of this clone is 3575nucleotides long (FIG. 50; SEQ ID NO: 41). The open reading frame ofthis cDNA, nucleotides 59 to 928 of SEQ ID NO: 66, (SEQ ID NO: 41),encodes a 290 amino acid transmembrane protein (FIG. 50; SEQ ID NO: 42).

[0494]FIG. 51 depicts a hydropathy plot of human TANGO 509, the detailsof which are described herein.

[0495] The signal peptide prediction program SIGNALP (Nielsen et al.,1997, Protein Engineering 10:1-6) predicted that human TANGO 509includes a 18 amino acid signal peptide (amino acid 1 to amino acid 18of SEQ ID NO: 42) preceding the mature TANGO 509 protein (correspondingto amino acid 19 to amino acid 290 of SEQ ID NO: 42). In instanceswherein the signal peptide is cleaved, the molecular weight of TANGO 509protein without post-translational modifications is 33.3 kDa prior tothe cleavage of the signal peptide, and 31.0 kDa after cleavage of thesignal peptide.

[0496] Human TANGO 509 protein is a transmembrane protein that containsan extracellular domain at amino acid residues 260 to 290, atransmembrane domain at amino acid residues 241 to 259, and acytoplasmic domain at amino acid residues 19 to 240 of SEQ ID NO: 42.

[0497] In instances wherein the signal peptide is not cleaved, humanTANGO 509 contains an extracellular domain at amino acid residues 260 to290, a transmembrane domain at amino acid residues 241 to 259, and acytoplasmic domain at amino acid residues 1 to 240 of SEQ ID NO: 42.

[0498] Alternatively, in another embodiment, a human TANGO 509 proteincontains a cytoplasmic domain at amino acid residues 260 to 290, atransmembrane domain at amino acid residues 241 to 259, and anextracelluar domain at amino acid residues 19 to 240 of SEQ ID NO: 42.

[0499] A human TANGO 509 family member can include one or more of thefollowing domains: (1) an extracellular domain; (2) a transmembranedomain; and (3) a cytoplasmic domain. In one embodiment, a human TANGO509 protein contains an extracellular domain at about amino acidresidues 19 to 240, a transmembrane domain at about amino acid residues241 to 259, and a cytoplasmic domain at about amino acid residues 260 to290 of SEQ ID NO: 42. In this embodiment, the mature TANGO 509 proteincorresponds to amino acids 19 to 290 of SEQ ID NO: 42.

[0500] A human TANGO 509 family member can include a signal sequence. Incertain embodiments, a human TANGO 509 family member has the amino acidsequence of SEQ ID NO: 42, and the signal sequence is located at aboutamino acids 1 to 16, 1 to 17, 1 to 18, 1 to 19, or 1 to 20. In suchembodiments of the invention, the domains and the mature proteinresulting from cleavage of such signal peptides are also includedherein. For example, the cleavage of a signal sequence consisting ofamino acids 1 to 18 results in a mature human TANGO 509 proteincorresponding to amino acids 19 to 290 of SEQ ID NO: 42.

[0501] A human TANGO 509 family member can include one or more Ig-likedomains. A TANGO 509 Ig-like domain as described herein has thefollowing consensus sequence, beginning about 1 to 15 amino acidresidues, more preferably about 3 to 10 amino acid residues, and mostpreferably about 5 amino acid residues from the domain C-terminus:[FY]-Xaa-C, wherein [FY] is either a phenylalanine or a tyrosine residue(preferably tyrosine), where “Xaa” is any amino acid, and C is acysteine residue. In one embodiment, a human TANGO 509 family memberincludes one or more Ig-like domains having an amino acid sequence thatis at least about 55%, preferably at least about 65%, more preferably atleast 75%, yet more preferably at least about 85%, and most preferablyat least about 95% identical to amino acids 33 to 116 or 148 to 211 ofSEQ ID NO: 42.

[0502] In another embodiment, a human TANGO 509 family member includesone or more TANGO 509 Ig-like domains having an amino acid sequence thatis at least about 55%, preferably at least about 65%, more preferably atleast about 75%, yet more preferably at least about 85%, and mostpreferably at least about 95% identical to amino acids 33 to 116 or 148to 211 of SEQ ID NO: 42, and has a conserved cysteine residue about 8residues downstream from the N-terminus of the Ig-like domain. Inanother embodiment, a human TANGO 509 family member includes one or moreTANGO 509 Ig-like domains having an amino acid sequence that is at least55%, preferably at least about 65%, more preferably at least about 75%,yet more preferably at least about 85%, and most preferably at leastabout 95% identical to amino acids 33 to 116 or 148 to 211 of SEQ ID NO:42, has a conserved cysteine residue about 8 residues downstream fromthe N-terminus of the Ig-like domain and has a conserved cysteine withinthe consensus sequence that forms a disulfide with said first conservedcysteine.

[0503] In yet another embodiment, a human TANGO 509 family memberincludes one or more TANGO 509 Ig-like domains having an amino acidsequence that is at least 55%, preferably at least about 65%, morepreferably at least about 75%, yet more preferably at least about 85%,and most preferably at least about 95% identical to amino acids 33 to116 or 148 to 211 of SEQ ID NO: 42, and has a conserved cysteine residueabout 8 residues downstream from the N-terminus of the Ig-like domainwhich has a conserved cysteine within the consensus sequence that formsa disulfide with said first conserved cysteine, and has at least onehuman TANGO 509 biological activity as described herein.

[0504] In another embodiment, the Ig-like domain of human TANGO 509 isan Ig-like domain which has the following consensus sequence at theC-terminus of the domain: [FY]-Xaa-C-Xaa-[VAIF]—COO—, wherein [FY] iseither a phenylalanine or a tyrosine residue (preferably tyrosine),where “Xaa” is any amino acid, C is a cysteine residue, [VA] is avaline, an alanine, an isoleucine or phenylalanine residue, and COO— isthe C-terminus of the domain. In this embodiment, a human TANGO 509family member includes one or more of these Ig-like domains having anamino acid sequence that is at least about 55%, preferably at leastabout 65%, more preferably at least 75%, yet more preferably at leastabout 85%, and most preferably at least about 95% identical to aminoacids 33 to 116 or 148 to 211 of SEQ ID NO: 42.

[0505] In one embodiment a cDNA sequence of human TANGO 509 has anucleotide at position 69 which is thymidine (T). In this embodiment,the cDNA contains an open reading frame encoding a polypeptide having anamino acid at position 4 that is phenylalanine (F). In an alternativeembodiment, a species variant cDNA sequence of human TANGO 509 has anucleotide at position 69 which is adenine (A). In this embodiment, thecDNA contains an open reading frame encoding a polypeptide having anamino acid at position 4 that is tyrosine (Y), i.e., a conservativesubstitution.

[0506] In another embodiment a cDNA sequence of human TANGO 509 has anucleotide at position 72 which is cytosine (C). In this embodiment, thecDNA contains an open reading frame encoding a polypeptide having anamino acid at position 5 that is alanine (A). In an alternativeembodiment, a species variant cDNA sequence of human TANGO 509 has anucleotide at position 72 which is thymine (T). In this embodiment, thecDNA contains an open reading frame encoding a polypeptide having anamino acid at position 5 that is valine (V), i.e., a conservativesubstitution.

[0507] In another embodiment a cDNA sequence of human TANGO 509 has anucleotide at position 132 which is adenine (A). In this embodiment, thecDNA contains an open reading frame encoding a polypeptide having anamino acid at position 25 that is lysine (K). In an alternativeembodiment, a species variant cDNA sequence of human TANGO 509 has anucleotide at position 132 which is guanine (G). In this embodiment, thecDNA contains an open reading frame encoding a polypeptide having anamino acid at position 25 that is arginine (R), i.e., a conservativesubstitution.

[0508] In another embodiment a cDNA sequence of human TANGO 509 has anucleotide at position 191 which is guanine (G). In this embodiment, thecDNA contains an open reading frame encoding a polypeptide having anamino acid at position 45 that is glutamate (E). In an alternativeembodiment, a species variant cDNA sequence of human TANGO 509 has anucleotide at position 191 which is cytosine (C). In this embodiment,the cDNA contains an open reading frame encoding a polypeptide having anamino acid at position 45 that is glutamine (Q), i.e., a conservativesubstitution.

[0509] Human TANGO 509 has four N-glycosylation sites with the firstsequence NMTI (at amino acid residues 35 to 38), the second has thesequence NVTS (at amino acid residues 192 to 195), the third has thesequence NTTT (at amino acid residues 200 to 203), and the fourth hasthe sequence NHTA (at amino acid residues 219 to 222).

[0510] Two cAMP and cGMP-dependent protein kinase phosphorylation sitesare present in human TANGO 509. The first has the sequence KRIT (atamino acid residues 124 to 127), and the second has the sequence KKQS.

[0511] Seven protein kinase C phosphorylation sites are present in humanTANGO 509. The first has the sequence SYR (at amino acid residues 80 to82), the second has the sequence TVK (at amino acid residues 127 to129), the third has the sequence SGK (at amino acid residues 176 to178), the fourth has the sequence SKR (at amino acid residues 184 to186), the fifth has the sequence TLR (at amino acid residues 196 to198), the sixth has the sequence TFR (at amino acid residues 210 to212), and the seventh has the sequence SKK (at amino acid residues 279to 281).

[0512] Human TANGO 509 has five casein kinase II phosphorylation sites.The first has the sequence SEHE (at amino acid residues 149 to 152), thesecond has the sequence TSSD (at amino acid residues 168 to 171), thethird has the sequence SKRE (at amino acid residues 184 to 187), thefourth has the sequence TTNE (at amino acid residues 202 to 205 SEQ IDNO: 68), and the fifth has the sequence THLE (at amino acid residues 285to 288 SEQ ID NO: 68).

[0513] Human TANGO 509 has a tyrosine kinase phosphorylation site withthe sequence KLQDAGVY (at amino acid residues 105 to 112). Human TANGO509 has four N-myristoylation sites. The first has the sequence GSNMTI(at amino acid residues 33 to 38), the second has the sequence GVYRCM(at amino acid residues 110 to 115), the third has the sequence GVALTF(at amino acid residues 252 to 257), and fourth has the sequence GIQDTN(at amino acid residues 273 to 278).

[0514]FIG. 52 depicts an alignment of the human TANGO 509 amino acidsequence (SEQ ID NO: 42) with the butyrophilin-like amino acid sequence(SEQ ID NO: 48; Accession Number: AF142780). The alignment shows thatthere is a 33.0% overall amino acid sequence identity between TANGO 509and Butyrophilin-like protein. The Butyrophilin-like protein isexpressed in dendritic cells which are involved in such processes asantigen presentation and immune stimulation. As such TANGO 509 proteins,nucleic acids and modulators thereof could be useful in immunemodulation, for example in antigen presentation and immune stimulation.

[0515] Clone EpT509, which encodes human TANGO 509, was deposited withthe American Type Culture Collection (10801 University Boulevard,Manassas, Va. 20110-2209) on Aug. 5, 1999 and assigned Accession NumberPTA-438. This deposit will be maintained under the terms of the BudapestTreaty on the International Recognition of the Deposit of Microorganismsfor the Purposes of patent Procedure. This deposit was made merely as aconvenience for those of skill in the art and is not an admission that adeposit is required under 35 U.S.C. §112.

[0516] Mouse TANGO 509

[0517] A cDNA encoding mouse TANGO 509 was identified by analyzing thesequences of clones present in an alveolar macrophage cell line library.This analysis led to the identification of a clone, jtmca053b03,encoding mouse TANGO 509. The mouse TANGO 509 cDNA of this clone is 3637nucleotides long (FIG. 53; SEQ ID NO: 43). The open reading frame ofthis cDNA, nucleotides 49 to 918 of SEQ ID NO: 43, encodes a 290 aminoacid transmembrane protein (FIG. 53; SEQ ID NO: 44).

[0518]FIG. 54 depicts a hydropathy plot of mouse TANGO 509, the detailsof which are described herein.

[0519] The signal peptide prediction program SIGNALP (Nielsen et al.,1997, Protein Engineering 10:1-6) predicted that mouse TANGO 509includes a 18 amino acid signal peptide (amino acid 1 to amino acid 18of SEQ ID NO: 44) preceding the mature TANGO 509 protein (correspondingto amino acid 19 to amino acid 290 of SEQ ID NO: 44). In instanceswherein the signal peptide is cleaved, the molecular weight of TANGO 509about 65%, more preferably at least 75%, yet more preferably at leastabout 85%, and most preferably at least about 95% identical to aminoacids 33 to 116 of SEQ ID NO: 44.

[0520] In another embodiment, a mouse TANGO 509 family member includesone or more mouse TANGO 509 Ig-like domains having an amino acidsequence that is at least about 55%, preferably at least about 65%, morepreferably at least about 75%, yet more preferably at least about 85%,and most preferably at least about 95% identical to amino acids 33 to116 of SEQ ID NO: 44, and has a conserved cysteine residue about 8residues downstream from the N-terminus of the Ig-like domain. Inanother embodiment, a mouse TANGO 509 family member includes one or moremouse TANGO 509 Ig-like domains having an amino acid sequence that is atleast 55%, preferably at least about 65%, more preferably at least about75%, yet more preferably at least about 85%, and most preferably atleast about 95% identical to amino acids 33 to 116 of SEQ ID NO: 44, hasa conserved cysteine residue about 8 residues downstream from theN-terminus of the Ig-like domain, and has a conserved cysteine withinthe consensus sequence that forms a disulfide with said first conservedcysteine.

[0521] In yet another embodiment, a mouse TANGO 509 family memberincludes one or more Ig-like domains having an amino acid sequence thatis at least 55%, preferably at least about 65%, more preferably at leastabout 75%, yet more preferably at least about 85%, and most preferablyat least about 95% identical to amino acids 33 to 116 of SEQ ID NO: 44,and has a conserved cysteine residue about 8 residues downstream fromthe N-terminus of the Ig-like domain, has a conserved cysteine withinthe consensus sequence that forms a disulfide with said first conservedcysteine, and has at least one mouse TANGO 509 biological activity asdescribed herein.

[0522] In another embodiment, the Ig-like domain of mouse TANGO 509 isan Ig domain which has the following consensus sequence at theC-terminus of the domain: [FY]-Xaa-C-Xaa-[VAIF]—COO—, wherein [FY] iseither a phenylalanine or a tyrosine residue (preferably tyrosine),where “Xaa” is any amino acid, C is a cysteine residue, [VA] is avaline, an alanine, an isoleucine or phenylalanine residue, and COO— isthe C-terminus of the domain. In this embodiment, a mouse TANGO 509family member includes one or more Ig-like domains having an amino acidsequence that is at least about 55%, preferably at least about 65%, morepreferably at least 75%, yet more preferably at least about 85%, andmost preferably at least about 95% identical to amino acids 33 to 116 ofSEQ ID NO: 44.

[0523] In one embodiment a cDNA sequence of mouse TANGO 509 has anucleotide at position 65 which is thymidine (T). In this embodiment,the cDNA contains an open reading frame encoding a polypeptide having anamino acid at position 4 that is phenylalanine (F). In an alternativeembodiment, a species variant cDNA sequence of mouse TANGO 509 has anucleotide at position 65 which is adenine (A). In this embodiment, thecDNA contains an open reading frame encoding a polypeptide having anamino acid at position 4 that is tyrosine (Y), i.e., a conservativesubstitution.

[0524] In another embodiment a cDNA sequence of mouse TANGO 509 has anucleotide at position 68 which is cytosine (C). In this embodiment, thecDNA contains an open reading frame encoding a polypeptide having anamino acid at position 5 that is alanine (A). In an alternativeembodiment, a species variant cDNA sequence of mouse TANGO 509 has anucleotide at position 68 which is thymine (T). In this embodiment, thecDNA contains an open reading frame encoding a polypeptide having anamino acid at position 5 that is valine (V), i.e., a conservativesubstitution.

[0525] In another embodiment a cDNA sequence of mouse TANGO 509 has anucleotide at position 128 which is adenine (A). In this embodiment, thecDNA contains an open reading frame encoding a polypeptide having anamino acid at position 25 that is lysine (K). In an alternativeembodiment, a species variant cDNA sequence of mouse TANGO 509 has anucleotide at position 128 which is guanine (G). In this embodiment, thecDNA contains an open reading frame encoding a polypeptide having anamino acid at position 25 that is arginine (R), i.e., a conservativesubstitution.

[0526] In another embodiment a cDNA sequence of mouse TANGO 509 has anucleotide at position 132 which is cytosine (C). In this embodiment,the cDNA contains an open reading frame encoding a polypeptide having anamino acid at position 26 that is aspartate (D). In an alternativeembodiment, a species variant cDNA sequence of mouse TANGO 509 has anucleotide at position 132 which is adenine (A). In this embodiment, thecDNA contains an open reading frame encoding a polypeptide having anamino acid at position 45 that is glutamate (E), i.e., a conservativesubstitution.

[0527] Mouse TANGO 509 has six N-glycosylation sites with the firstsequence NVTM (at amino acid residues 35 to 38), the second has thesequence NVTS (at amino acid residues 191 to 194), the third has thesequence NATA (at amino acid residues 199 to 202), the fourth has thesequence NHTA (at amino acid residues 218 to 221), the fifth has thesequence NRTH (at amino acid residues 236 to 239), and the sixth has thesequence NDTQ (at amino acid residues 283 to 286).

[0528] Mouse TANGO 509 has one cAMP and cGMP-dependent protein kinasephosphorylation site, having the sequence KRIT (at amino acid residues124 to 127).

[0529] Mouse TANGO 509 has five protein kinase C phosphorylation sites.The first has the sequence TLK (at amino acid residues 127 to 129), thesecond has the sequence SGK (at amino acid residues 175 to 177), thethird has the sequence TSR (at amino acid residues 182 to 184), thefourth has the sequence SLR (at amino acid residues 195 to 197), and thefifth has the sequence SSK (at amino acid residues 278 to 280).

[0530] Mouse TANGO 509 has five casein kinase II phosphorylation sites.The first has the sequence SEHE (at amino acid residues 148 to 151), thesecond has the sequence TNSD (at amino acid residues 167 to 170), thethird has the sequence SRTE (at amino acid residues 183 to 186), thefourth has the sequence TAND (at amino acid residues 201 to 204), andthe fifth has the sequence TQFE (at amino acid residues 285 to 288).

[0531] Mouse TANGO 509 has a tyrosine kinase phosphorylation site withthe sequence KLQDAGVY (at amino acid residues 105 to 112).

[0532] Mouse TANGO 509 has five N-myristoylation sites. The first hasthe sequence GIIFTA (at amino acid residues 6 to 11), the second has thesequence GSNVTM (at amino acid residues 33 to 38), the third has thesequence GVYCCI (at amino acid residues 110 to 115 SEQ ID NO: 78), thefourth has the sequence GMLLNV (at amino acid residues 187 to 192), thefifth has the sequence GQNHTA (at amino acid residues 216 to 221), andthe sixth has the sequence GVEDTS (at amino acid residues 273 to 278).

[0533]FIG. 55 depicts an alignment of the mouse TANGO 509 amino acidsequence (SEQ ID NO: 44) with the butyrophilin-like protein amino acidsequence (SEQ ID NO: 48; Accession Number AF142780). The alignment showsthat there is a 31.9% overall amino acid sequence identity between mouseTANGO 509 and the butyrophilin-like protein. This alignment wasperformed using the ALIGN alignment program with a PAM120 scoringmatrix, a gap length penalty of 12, and a gap penalty of 4.

[0534] Uses of TANGO 509 Nucleic Acids, Polypeptides, and ModulatorsThereof

[0535] As human TANGO 509 was originally found in a mammary epitheliallibrary, TANGO 509 nucleic acids, proteins, and modulators thereof canbe used to modulate the proliferation, activation, development,differentiation, and/or function of mammary cells, tissues and/ororgans, e.g., tissues and cells of mammary epithelium origin. TANGO 509nucleic acids, proteins and modulators thereof can be used to treatmammary-related disorders, e.g., breast cancer.

[0536] TANGO 509 exhibits homology to butyrophilin (BTN). BTN is themajor protein associated with fat droplets in the milk of many species.BTN has immunoglobulin-like domains and is specifically expressed on theapical surface of mammary epithelial cells during lactation and becomesincorporated as an integral protein into the membrane of the milk fatglobule during the budding and secretion of fat droplets into milk. Assuch, TANGO 509 nucleic acids, proteins and modulators thereof can beutilized to modulate fat secretion, e.g., fat secretion by the mammaryepithelium, and milk secretion. In addition, such TANGO 509 compositionsand modulators thereof can be used to bind to and, e.g., enhance,deplete or purify milk-associated factors. Further, TANGO 509 nucleicacids, proteins and modulators thereof can be utilized to treat mammaryepithelium secretory diseases and/or disorders.

[0537] As mouse TANGO 509 was isolated from an alveolar macrophagelibrary, and in light of the fact that TANGO 509 family members havecharacteristics of immunoglobulin superfamily proteins which are cellsurface molecules involved in signal transduction and cellularproliferation, TANGO 509 nucleic acids, proteins and modulators thereofcan be utilized to modulate the development and progression of cancerousand non-cancerous cell proliferative disorders, such as deregulatedproliferation (such as hyperdysplasia, hyper-IgM syndrome, orlymphoproliferative disorders), cirrhosis of the liver (a condition inwhich scarring has overtaken normal liver regeneration processes),treatment of keloid (hypertrophic scar) formation (disfiguring of theskin in which the scarring process interferes with normal renewal),psoriasis (a common skin condition characterized by excessiveproliferation of the skin and delay in proper cell fate determination),benign tumors, fibrocystic conditions, and tissue hypertrophy (e.g.,prostatic hyperplasia), cancers such as neoplasms or tumors (such ascarcinomas, sarcomas, adenomas or myeloid lymphoma tumors, e.g.,fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenicsarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma,lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor,leimyosarcoma, rhabdotheliosarcoma, colon sarcoma, pancreatic cancer,breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma,basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceousgland carcinoma, papillary carcinoma, papillary adenocarcinomas,cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renalcell carcinoma, hematoma, bile duct carcinoma, melanoma,choriocarcinoma, semicoma, embryonal carcinoma, Wilms' tumor, cervicalcancer, testicular tumor, lung carcinoma, small cell carcinoma, bladdercarcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma,craniopharyngioma, ependynoma, pinealoma, hemangioblastoma,retinoblastoma), leukemias, (e.g. acute lymphocytic leukemia), acutemyelocytic leukemia (myelolastic, promyelocytic, myelomonocytic,monocytic and erythroleukemia), chronic leukemias (chronic myelocytic(granulocytic) leukemia and chronic lymphocytic leukemia), orpolycythemia vera, or lymphomas (Hodgkin's disease and non-Hodgkin'sdiseases), multiple myelomas and Waldenstrom's macroglobulinemia.

[0538] As TANGO 509 proteins exhibit similarity to immunoglobulindomains, TANGO 509 nucleic acids, proteins and modulators thereof can beutilized to modulate immune activation. For example, antagonists toTANGO 509 action, such as peptides, antibodies or small molecules thatdecrease or block TANGO 509 activity, e.g., binding to extracellularmatrix components, e.g., integrins, or that prevent TANGO 509 signaling,can be used as immune system activation blockers. In another example,agonists that mimic TANGO 509 activity, such as peptides, antibodies orsmall molecules, can be used to induce immune system activation.Antibodies may activate or inhibit the cell adhesion, proliferation andactivation, and may help in treating infection, autoimmunity,inflammation, and cancer by affecting these cellular processes. TANGO509 nucleic acids, proteins and modulators thereof can also be utilizedto modulate intercellular signaling in the immune system, e.g., modulateintercellular signal transduction in immune stimulation or suppressionand modulate immune cell membrane adhesion to ECM components, duringdevelopment, e.g., late stages of development.

[0539] As TANGO 509 family members exhibit homology with the immuneco-stimulatory molecules, CD80 and CD86, TANGO 509 nucleic acids,proteins and modulators thereof can be used for modulation of lymphocyteactivation, cytokine secretion, e.g., IL-2, B-cell selection andmaturation, as well as T-cell selection and maturation. TANGO 509nucleic acids, proteins and modulators thereof can also be used to treatsubjects infected with a pathogen, or to modulate autoimmune diseases,e.g., rheumatoid arthritis, Morbus Bechterew, Sjogren's Syndrome, andulcerative colitis.

[0540] Furthermore, TANGO 509 nucleic acids, proteins and modulatorsthereof can be used for immune cell receptor co-stimulation via CD28 tomodulate IL-2 expression in addition to modulating the expression ofother lymphokines. Moreover, TANGO 509 nucleic acids, proteins andmodulators thereof can be used to modulate diseases of the immunesystem, in particular AIDS, asthma or chronic viral diseases such ashepatitis C virus or hepatitis B virus infections, or to modulate theimmune system in cancer patients, or patients undergoing organ or tissuetransplantation procedures, or inflammatory disorders, e.g., bacterialor viral infection, psoriasis, septicemia, arthritis, allergicreactions.

[0541] TANGO 509 expression can be utilized as a marker (e.g., an insitu marker) for specific tissues (e.g., the mammary glands) and/orcells (e.g., mammary epithelial cells) in which TANGO 509 is expressed.TANGO 509 nucleic acids can also be utilized for chromosomal mapping, oras chromosomal markers, e.g., in radiation hybrid mapping.

[0542] TABLE 1: Summary of Nucleotide Sequence Information of TANGO 239,TANGO 219, TANGO 232, TANGO 281, A236 (INTERCEPT 236), TANGO 300, TANGO353, TANGO 393, TANGO 402, TANGO 351 and TANGO 509 Nucleic Acids.protein without post-translational modifications is 33.3 kDa prior tothe cleavage of the signal peptide, and 31.0 kDa after cleavage of thesignal peptide.

[0543] Mouse TANGO 509 protein is a transmembrane protein that containsan extracellular domain at amino acid residues 261 to 290, atransmembrane domain at amino acid residues 240 to 260, and acytoplasmic domain at amino acid residues 19 to 239 of SEQ ID NO: 44.

[0544] In instances wherein the signal peptide is not cleaved, mouseTANGO 509 contains an extracellular domain at amino acid residues 261 to290, a transmembrane domain at amino acid residues 240 to 260, and acytoplasmic domain at amino acid residues 1 to 239 of SEQ ID NO: 44.

[0545] Alternatively, in another embodiment, a mouse TANGO 509 proteincontains a cytoplasmic domain at amino acid residues 261 to 290, atransmembrane domain at amino acid residues 240 to 260, and anextracellular domain at amino acid residues 19 to 239 of SEQ ID NO: 44.

[0546] A mouse TANGO 509 family member can include one or more of thefollowing domains: (1) an extracellular domain; (2) a transmembranedomain; and (3) a cytoplasmic domain. In one embodiment, a mouse TANGO509 protein contains an extracellular domain consisting of amino acids19 to 239, a transmembrane domain at amino acids 240 to 260, acytoplasmic domain at amino acids 261 to 290 and a mature mouse TANGO509 protein at amino acids 19 to 290 of SEQ ID NO: 44.

[0547] A mouse TANGO 509 family member can include a signal sequence. Incertain embodiments, a TANGO 509 family member has the amino acidsequence of SEQ ID NO: 44, and the signal sequence is located at aboutamino acids 1 to 16, 1 to 17, 1 to 18, 1 to 19, or 1 to 20. In suchembodiments of the invention, the domains and the mature proteinresulting from cleavage of such signal peptides are also includedherein. For example, the cleavage of a signal sequence consisting ofamino acids 1 to 18 results in a mature mouse TANGO 509 proteincorresponding to amino acids 19 to 290 of SEQ ID NO: 44.

[0548] A mouse TANGO 509 family member can include one or more Ig-likedomains. A mouse TANGO 509 Ig-like domain as described herein has thefollowing consensus sequence, beginning about 1 to 15 amino acidresidues, more preferably about 3 to 10 amino acid residues, and mostpreferably about 5 amino acid residues from the domain C-terminus:[FY]-Xaa-C, wherein [FY] is either a phenylalanine or a tyrosine residue(preferably tyrosine), where “Xaa” is any amino acid, and C is acysteine residue. In one embodiment, a mouse TANGO 509 family memberincludes one or more such Ig-like domains having an amino acid sequencethat is at least about 55%, preferably at least (OPEN ATCC READINGACCES- FRAME) POLY- SION GENE FIG. and cDNA PEPTIDE NUMBER h TANGO 239, 1  (344 to 1990), 550 amino acids  98999 form 1 3413 base pair (a.a.);(b.p).;  SEQ ID NO:2  SEQ ID NO: 1 h TANGO 239,  4  (344-2401), 686a.a.; form 2 3413 b.p.;  SEQ ID NO: 4  SEQ ID NO: 3 m TANGO 239  5(209-370),  54 a.a.; 1029 b.p.;  SEQ ID NO: 6  SEQ ID NO: 5 h TANGO 219 6 (106 to 552), 149 a.a.;  98899 1268 b.p.;  SEQ ID NO: 8  SEQ ID NO: 7m TANGO 219  8  (2 to 370), 123 a.a.;  397 b.p.; SEQ ID NO: 10  SEQ IDNO: 9 macaque  9  (96 to 809), 238 a.a.; 207045 TANGO 232 1932 b.p.; SEQID NO: 12 SEQ ID NO: 11 h TANGO 232, 12  (1 to 366), 122 a.a.; 207046form 1 1459 b.p.; SEQ ID NO: 14 SEQ ID NO: 13 h TANGO 232, 15 (110 to823), 238 a.a.; form 2  238 b.p.; SEQ ID NO: 16 SEQ ID NO: 15 m TANGO232 16  (79 to 795), 239 a.a.; 2221 b.p.; SEQ ID NO: 18 SEQ ID NO: 17 hTANGO 281 17  (65 to 799); 245 a.a.; 207222 1812 b.p.; SEQ ID NO: 20 SEQID NO: 19 m TANGO 281 20 (90 to 728), 213 a.a.; PTA-224 1858 b.p.; SEQID NO: 22 SEQ ID NO: 21 h A236 23  (314 to 1432), 373 a.a.;  PTA-34 (hIN- 1948 b.p.; SEQ ID NO: 24 TERCEPT SEQ ID NO: 23 236) m A236 26  (304to 1422), 373 a.a.; (m IN- 1949 b.p.; SEQ ID NO: 26 TERCEPT SEQ ID NO:25 236) h TANGO 300 30  (31 to 1113), 361 a.a.; PTA-293 1332 b.p.; SEQID NO: 28 SEQ ID NO: 27 m TANGO 300 32  (41 to 1195), 385 a.a.; 1400b.p.; SEQ ID NO: 30 SEQ ID NO: 29 h TANGO 353 36  (76 to 765), 230 a.a.;PTA-292 1239 b.p.; SEQ ID NO: 32 SEQ ID NO: 31 h TANGO 393 38  (40 to1458), 473 a.a.; PTA-295 1778 b.p.; SEQ ID NO: 34 SEQ ID NO: 33 m TANGO393 40  (226 to 1644), 473 a.a.; 1946 b.p.; SEQ ID NO: 36 SEQ ID NO: 35h TANGO 402 44  (87 to 707), 207 a.a.; PTA-294 1348 b.p.; SEQ ID NO: 38SEQ ID NO: 37 h TANGO 351 48  (143 to 1588), 482 a.a.; PTA-424 3345b.p.; SEQ ID NO: 40 SEQ ID NO: 39 h TANGO 509 50  (59 to 928), 290 a.a.;PTA-438 3575 b.p.; SEQ ID NO: 42 SEQ ID NO: 41 m TANGO 509 53  (49 to918), 290 a.a.; 3637 b.p.; SEQ ID NO: 44 SEQ ID NO: 43

[0549] Various aspects of the invention are described in further detailin the following subsections:

[0550] I. Isolated Nucleic Acid Molecules

[0551] One aspect of the invention pertains to isolated nucleic acidmolecules that encode a polypeptide of the invention or a biologicallyactive portion thereof, as well as nucleic acid molecules sufficient foruse as hybridization probes to identify nucleic acid molecules encodinga polypeptide of the invention and fragments of such nucleic acidmolecules suitable for use as PCR primers for the amplification ormutation of nucleic acid molecules. As used herein, the term “nucleicacid molecule” is intended to include DNA molecules (e.g., cDNA orgenomic DNA) and RNA molecules (e.g., MRNA) and analogs of the DNA orRNA generated using nucleotide analogs. The nucleic acid molecule can besingle-stranded or double-stranded, but preferably is double-strandedDNA.

[0552] An “isolated” nucleic acid molecule is one which is separatedfrom other nucleic acid molecules which are present in the naturalsource of the nucleic acid molecule. Preferably, an “isolated” nucleicacid molecule is free of sequences (preferably protein encodingsequences) which naturally flank the nucleic acid (i.e., sequenceslocated at the 5′ and 3′ ends of the nucleic acid) in the genomic DNA ofthe organism from which the nucleic acid is derived. For example, invarious embodiments, the isolated nucleic acid molecule can contain lessthan about 5 kB, 4 kB, 3 kB, 2 kB, 1 kB, 0.5 kB or 0.1 kB of nucleotidesequences which naturally flank the nucleic acid molecule in genomic DNAof the cell from which the nucleic acid is derived. Moreover, an“isolated” nucleic acid molecule, such as a cDNA molecule, can besubstantially free of other cellular material, or culture medium whenproduced by recombinant techniques, or substantially free of chemicalprecursors or other chemicals when chemically synthesized. As usedherein, the term “isolated” when referring to a nucleic acid moleculedoes not include an isolated chromosome.

[0553] In instances wherein the nucleic acid molecule is a cDNA or RNA,e.g., mRNA, molecule, such molecules can include a poly A “tail”, or,alternatively, can lack such a 3′ tail. Although cDNA or RNA nucleotidesequences may be depicted herein with such tail sequences, it is to beunderstood that cDNA nucleic acid molecules of the invention are alsointended to include such sequences lacking the depicted poly A tails.

[0554] All or a portion of the nucleic acid sequences of SEQ ID NO: 1,3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39,41, 43, or a complement thereof, can be used as molecular weight markerswhen compared to a comparably sized nucleic acid sequence. Likewise, allor a portion of the amino acid sequences encoded by SEQ ID NO: 1, 3, 5,7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41 ora complement thereof can be used as molecular weight markers, inparticular as molecular weight markers on SDS-PAGE electrophoresis.

[0555] A nucleic acid molecule of the present invention, e.g., a nucleicacid molecule having the nucleotide sequence of SEQ ID NO: 1, 3, 5, 7,9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, or acomplement thereof, can be isolated using standard molecular biologytechniques and the sequence information provided herein. Using all or aportion of the nucleic acid sequences of SEQ ID NO: 1, 3, 5, 7, 9, 11,13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, or 41, as ahybridization probe, nucleic acid molecules of the invention can beisolated using standard hybridization and cloning techniques (e.g., asdescribed in Sambrook et al., eds., Molecular Cloning: A LaboratoryManual, 2nd ed., Cold Spring Harbor Laboratory, Cold Spring HarborLaboratory Press, Cold Spring Harbor, N.Y., 1989).

[0556] A nucleic acid molecule of the invention can be amplified usingcDNA, mRNA or genomic DNA as a template and appropriate oligonucleotideprimers according to standard PCR amplification techniques. The nucleicacid so amplified can be cloned into an appropriate vector andcharacterized by DNA sequence analysis. Furthermore, oligonucleotidescorresponding to all or a portion of a nucleic acid molecule of theinvention can be prepared by standard synthetic techniques, e.g., usingan automated DNA synthesizer.

[0557] In another preferred embodiment, an isolated nucleic acidmolecule of the invention comprises a nucleic acid molecule which is acomplement of the nucleotide sequence of SEQ ID NO: 1, 3, 5, 7, 9, 11,13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, or a portionthereof. A nucleic acid molecule which is complementary to a givennucleotide sequence is one which is sufficiently complementary to thegiven nucleotide sequence that it can hybridize to the nucleotidesequence under the conditions set forth herein, thereby forming a stableduplex.

[0558] Moreover, a nucleic acid molecule of the invention can compriseonly a portion of a nucleic acid sequence encoding a full lengthpolypeptide of the invention for example, a fragment which can be usedas a probe or primer or a fragment encoding a biologically activeportion of a polypeptide of the invention. The nucleotide sequencedetermined from the cloning one gene allows for the generation of probesand primers designed for use in identifying and/or cloning homologs inother cell types, e.g., from other tissues, as well as homologs fromother mammals. The probe/primer typically comprises substantiallypurified oligonucleotide. In one embodiment, the oligonucleotidetypically comprises a region of nucleotide sequence that hybridizesunder stringent conditions to at least about 12, preferably about 25,more preferably about 50, 75, 100, 125, 150, 175, 200, 250, 300, 350 or400 contiguous nucleotides of the sense or anti-sense sequence of SEQ IDNO: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35,37, 39, 41, of a naturally occurring mutant of SEQ ID NO: 1, 3, 5, 7, 9,11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41. Inanother embodiment, the oligonucleotide comprises a region of nucleotidesequence that hybridizes under stringent conditions to at least 400,preferably 450, 500, 530, 550, 600, 700, 800, 900, 1000 or 1150consecutive oligonucleotides of the sense or antisense sequence of SEQID NO: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33,35, 37, 39, 41, of a naturally occurring mutant of SEQ ID NO: 1, 3, 5,7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41.

[0559] Probes based on the sequence of a nucleic acid molecule of theinvention can be used to detect transcripts or genomic sequencesencoding the same protein molecule encoded by a selected nucleic acidmolecule. The probe comprises a label group attached thereto, e.g., aradioisotope, a fluorescent compound, an enzyme, or an enzyme co-factor.Such probes can be used as part of a diagnostic test kit for identifyingcells or tissues which mis-express the protein, such as by measuringlevels of a nucleic acid molecule encoding the protein in a sample ofcells from a subject, e.g., detecting mRNA levels or determining whethera gene encoding the protein has been mutated or deleted.

[0560] A nucleic acid fragment encoding a biologically active portion ofa polypeptide of the invention can be prepared by isolating a portion ofany of SEQ ID NO: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29,31, 33, 35, 37, 39, 41 or 43, expressing the encoded portion of thepolypeptide protein (e.g., by recombinant expression in vitro) andassessing the activity of the encoded portion of the polypeptide.

[0561] The invention further encompasses nucleic acid molecules thatdiffer from the nucleotide sequence of SEQ ID NO: SEQ ID NO: 1, 3, 5, 7,9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41 or 43due to degeneracy of the genetic code and thus encode the same proteinas that encoded by the nucleotide sequence of SEQ ID NO: 1, 3, 5, 7, 9,11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41 or 43.

[0562] In addition to the nucleotide sequences of SEQ ID NO: 1, 3, 5, 7,9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41 or 43,it will be appreciated by those skilled in the art that DNA sequencepolymorphisms that lead to changes in the amino acid sequence may existwithin a population (e.g., the human population). Such geneticpolymorphisms may exist among individuals within a population due tonatural allelic variation.

[0563] An allele is one of a group of genes which occur alternatively ata given genetic locus. As used herein, the phrase “allelic variant”refers to a nucleotide sequence which occurs at a given locus or to apolypeptide encoded by the nucleotide sequence. As used herein, theterms “gene” and “recombinant gene” refer to nucleic acid moleculescomprising an open reading frame encoding a polypeptide of theinvention.

[0564] An allele is one of a group of genes which occur alternatively ata given genetic locus. As used herein, the phrase “allelic variant”refers to a nucleotide sequence which occurs at a given locus or to apolypeptide encoded by the nucleotide sequence.

[0565] For example, human TANGO 393 maps by homology to ESTs toChromosome 22 between D22S420 and D22S446; the human gene for TANGO 219was mapped on radiation hybrid panels to the long arm of chromosome 5,in the region q21-22; and human gene for TANGO 232 was mapped onradiation hybrid panels to the long arm of chromosome 11, in the regionq13.

[0566] Such natural allelic variations can typically result in 1-5%variance in the nucleotide sequence of a given gene. Alternative allelescan be identified by sequencing the gene of interest in a number ofdifferent individuals. This can be readily carried out by usinghybridization probes to identify the same genetic locus in a variety ofindividuals. Any and all such nucleotide variations and resulting aminoacid polymorphisms or variations that are the result of natural allelicvariation and that do not alter the functional activity are intended tobe within the scope of the invention. In one embodiment, polymorphismsthat are associated with a particular disease and/or disorder are usedas markers to diagnose said disease or disorder. In a preferredembodiment, polymorphisms are used as a marker to diagnose abnormalcoronary function such as atherosclerosis.

[0567] Moreover, nucleic acid molecules encoding proteins of theinvention from other species (homologs), which have a nucleotidesequence which differs from that of the human or mouse protein describedherein are intended to be within the scope of the invention. Nucleicacid molecules corresponding to natural allelic variants and homologs ofa cDNA of the invention can be isolated based on their identity to thehuman nucleic acid molecule disclosed herein using the human cDNA, or aportion thereof, as a hybridization probe according to standardhybridization techniques under stringent hybridization conditions. Forexample, a cDNA encoding a soluble form of a membrane-bound protein ofthe invention isolated based on its hybridization to a nucleic acidmolecule encoding all or part of the membrane-bound form. Likewise, acDNA encoding a membrane-bound form can be isolated based on itshybridization to a nucleic acid molecule encoding all or part of thesoluble form.

[0568] Accordingly, in another embodiment, an isolated nucleic acidmolecule of the invention is at least 500, 600, 700, 800, 900, 1000,1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900 or 2000 contiguousnucleotides in length and hybridizes under stringent conditions to thenucleic acid molecule comprising the nucleotide sequence, preferably thecoding sequence, of SEQ ID NO: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21,23, 25, 27, 29, 31, 33, 35, 37, 39, 41 or 43, or a complement thereof.

[0569] Accordingly, in another embodiment, an isolated nucleic acidmolecule of the invention is at least 25, 50, 100, 200, 300, 400, 500,600, 700, 800 or 900 contiguous nucleotides in length and hybridizesunder stringent conditions to the nucleic acid molecule comprising thenucleotide sequence, preferably the coding sequence, of SEQ ID NO: 1, 3,5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41or 43, or a complement thereof.

[0570] As used herein, the term “hybridizes under stringent conditions”is intended to describe conditions for hybridization and washing underwhich nucleotide sequences at least 60% (65%, 70%, preferably 75%)identical to each other typically remain hybridized to each other. Suchstringent conditions are known to those skilled in the art and can befound in Current Protocols in Molecular Biology, John Wiley & Sons, N.Y.(1989), 6.3.1-6.3.6. A preferred, non-limiting example of stringenthybridization conditions are hybridization in 6×sodium chloride/sodiumcitrate (SSC) at about 45° C. followed by one or more washes in 0.2×SSC,0.1% SDS at 50-65° C. Preferably, an isolated nucleic acid molecule ofthe invention that hybridizes under stringent conditions to the sequenceof SEQ ID NO: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31,33, 35, 37, 39, 41 or 43 or a complement thereof, corresponds to anaturally-occurring nucleic acid molecule. As used herein, a“naturally-occurring” nucleic acid molecule refers to an RNA or DNAmolecule having a nucleotide sequence that occurs in nature (e.g.,encodes a natural protein).

[0571] In addition to naturally-occurring allelic variants of a nucleicacid molecule of the invention sequence that may exist in thepopulation, the skilled artisan will further appreciate that changes canbe introduced by mutation thereby leading to changes in the amino acidsequence of the encoded protein, without altering the biologicalactivity of the protein. For example, one can make nucleotidesubstitutions leading to amino acid substitutions at “non-essential”amino acid residues. A “non-essential” amino acid residue is a residuethat can be altered from the wild-type sequence without altering thebiological activity, whereas an “essential” amino acid residue isrequired for biological activity. For example, amino acid residues thatare not conserved or only semi-conserved among homologs of variousspecies may be non-essential for activity and thus would be likelytargets for alteration. Alternatively, amino acid residues that areconserved among the homologs of various species (e.g., mouse and human)may be essential for activity and thus would not be likely targets foralteration.

[0572] Accordingly, another aspect of the invention pertains to nucleicacid molecules encoding a polypeptide of the invention that containchanges in amino acid residues that are not essential for activity. Suchpolypeptides differ in amino acid sequence from SEQ ID NO: 2, 4, 6, 8,10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, and44, yet retain biological activity. In one embodiment, the isolatednucleic acid molecule includes a nucleotide sequence encoding a proteinthat includes an amino acid sequence that is at least about 30%, 35%,40%, 45%, 50%, 55%, 60%, 65%, 75%, 85%, 95%, 98% identical to the aminoacid sequence of SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24,26, 28, 30, 32, 34, 36, 38, 40, 42, and 44.

[0573] An isolated nucleic acid molecule encoding a variant protein canbe created by introducing one or more nucleotide substitutions,additions or deletions into the nucleotide sequence of SEQ ID NO: 1, 3,5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41or 43, such that one or more amino acid substitutions, additions ordeletions are introduced into the encoded protein. Mutations can beintroduced by standard techniques, such as site-directed mutagenesis andPCR-mediated mutagenesis. Preferably, conservative amino acidsubstitutions are made at one or more predicted non-essential amino acidresidues. A “conservative amino acid substitution” is one in which theamino acid residue is replaced with an amino acid residue having asimilar side chain. Families of amino acid residues having similar sidechains have been defined in the art. These families include amino acidswith basic side chains (e.g., lysine, arginine, histidine), acidic sidechains (e.g., aspartic acid, glutamic acid, asparagine, glutamine),uncharged polar side chains (e.g., glycine, serine, threonine, tyrosine,cysteine), nonpolar side chains (e.g., alanine, valine, leucine,isoleucine, proline, phenylalanine, methionine, tryptophan),beta-branched side chains (e.g., threonine, valine, isoleucine) andaromatic side chains (e.g., tyrosine, phenylalanine, tryptophan,histidine). Alternatively, mutations can be introduced randomly alongall or part of the coding sequence, such as by saturation mutagenesis,and the resultant mutants can be screened for biological activity toidentify mutants that retain activity. Following mutagenesis, theencoded protein can be expressed recombinantly and the activity of theprotein can be determined.

[0574] In a preferred embodiment, a mutant polypeptide that is a variantof a polypeptide of the invention can be assayed for: (1) the ability toform protein-protein interactions with proteins in a signaling pathwayof the polypeptide of the invention; (2) the ability to bind a ligand ofthe polypeptide of the invention (i.e., in transmembrane proteins of theinvention or alternatively, secreted proteins which are the ligand for acellular receptor); or (3) the ability to bind to an intracellulartarget protein of the polypeptide of the invention. In yet anotherpreferred embodiment, the mutant polypeptide can be assayed for theability to modulate cellular proliferation, cellular migration, motilityor chemotaxis, or cellular differentiation.

[0575] The present invention encompasses antisense nucleic acidmolecules, i.e., molecules which are complementary to a sense nucleicacid encoding a polypeptide of the invention, e.g., complementary to thecoding strand of a double-stranded cDNA molecule or complementary to anmRNA sequence. Accordingly, an antisense nucleic acid can hydrogen bondto a sense nucleic acid. The antisense nucleic acid can be complementaryto an entire coding strand, or to only a portion thereof, e.g., all orpart of the protein coding region (or open reading frame). An antisensenucleic acid molecule can be antisense to all or part of a non-codingregion of the coding strand of a nucleotide sequence encoding apolypeptide of the invention. The non-coding regions (“5′ and 3′untranslated regions”) are the 5′ and 3′ sequences which flank thecoding region and are not translated into amino acids.

[0576] An antisense oligonucleotide can be, for example, about 5, 10,15, 20, 25, 30, 35, 40, 45 or 50 nucleotides or more in length. Anantisense nucleic acid of the invention can be constructed usingchemical synthesis and enzymatic ligation reactions using proceduresknown in the art. For example, an antisense nucleic acid (e.g., anantisense oligonucleotide) can be chemically synthesized using naturallyoccurring nucleotides or variously modified nucleotides designed toincrease the biological stability of the molecules or to increase thephysical stability of the duplex formed between the antisense and sensenucleic acids, e.g., phosphorothioate derivatives and acridinesubstituted nucleotides can be used. Examples of modified nucleotideswhich can be used to generate the antisense nucleic acid include5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil,hypoxanthine, xanthine, 4-acetylcytosine, 5-(carboxyhydroxylmethyl)uracil, 5-carboxymethylaminomethyl-2-thiouridine,5-carboxymethylaminomethyluracil, dihydrouracil,beta-D-galactosylqueosine, inosine, N6-isopentenyladenine,1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine,2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine,7-methylguanine, 5-methylaminomethyluracil,5-methoxyaminomethyl-2-thiouracil, beta-D-mannosylqueosine,5′-methoxycarboxymethyluracil, 5-methoxyuracil,2-methylthio-N6-isopentenyladenine, uracil-5-oxyacetic acid (v),wybutoxosine, pseudouracil, queosine, 2-thiocytosine,5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil,uracil-5-oxyacetic acid methylester, uracil-5-oxyacetic acid (v),5-methyl-2-thiouracil, 3-(3-amino-3-N-2-carboxypropyl) uracil, (acp3)w,and 2,6-diaminopurine. Alternatively, the antisense nucleic acid can beproduced biologically using an expression vector into which a nucleicacid has been subcloned in an antisense orientation (i.e., RNAtranscribed from the inserted nucleic acid will be of an antisenseorientation to a target nucleic acid of interest, described further inthe following subsection).

[0577] The antisense nucleic acid molecules of the invention aretypically administered to a subject or generated in situ such that theyhybridize with or bind to cellular mRNA and/or genomic DNA encoding aselected polypeptide of the invention to thereby inhibit expression,e.g., by inhibiting transcription and/or translation. The hybridizationcan be by conventional nucleotide complementarity to form a stableduplex, or, for example, in the case of an antisense nucleic acidmolecule which binds to DNA duplexes, through specific interactions inthe major groove of the double helix. An example of a route ofadministration of antisense nucleic acid molecules of the inventionincludes direct injection at a tissue site. Alternatively, antisensenucleic acid molecules can be modified to target selected cells and thenadministered systemically. For example, for systemic administration,antisense molecules can be modified such that they specifically bind toreceptors or antigens expressed on a selected cell surface, e.g., bylinking the antisense nucleic acid molecules to peptides or antibodieswhich bind to cell surface receptors or antigens. The antisense nucleicacid molecules can also be delivered to cells using the vectorsdescribed herein. To achieve sufficient intracellular concentrations ofthe antisense molecules, vector constructs in which the antisensenucleic acid molecule is placed under the control of a strong pol II orpol III promoter are preferred.

[0578] An antisense nucleic acid molecule of the invention can be anα-anomeric nucleic acid molecule. An α-anomeric nucleic acid moleculeforms specific double-stranded hybrids with complementary RNA in which,contrary to the usual β-units, the strands run parallel to each other(Gaultier et al. (1987) Nucleic Acids Res. 15:6625-6641). The antisensenucleic acid molecule can also comprise a 2′-o-methylribonucleotide(Inoue et al. (1987) Nucleic Acids Res. 15:6131-6148) or a chimericRNA-DNA analogue (Inoue et al. (1987) FEBS Lett. 215:327-330).

[0579] The invention also encompasses ribozymes. Ribozymes are catalyticRNA molecules with ribonuclease activity which are capable of cleaving asingle-stranded nucleic acid, such as an mRNA, to which they have acomplementary region. Thus, ribozymes (e.g., hammerhead ribozymes(described in Haselhoff and Gerlach, (1988), Nature 334:585-591)) can beused to catalytically cleave mRNA transcripts to thereby inhibittranslation of the protein encoded by the mRNA. A ribozyme havingspecificity for a nucleic acid molecule encoding a polypeptide of theinvention can be designed based upon the nucleotide sequence of a cDNAdisclosed herein. For example, a derivative of a Tetrahymena L-19 IVSRNA can be constructed in which the nucleotide sequence of the activesite is complementary to the nucleotide sequence to be cleaved in a Cechet al. U.S. Pat. No. 4,987,071; and Cech et al. U.S. Pat. No. 5,116,742.Alternatively, an mRNA encoding a polypeptide of the invention can beused to select a catalytic RNA having a specific ribonuclease activityfrom a pool of RNA molecules. See, e.g., Bartel and Szostak (1993)Science 261:1411-1418.

[0580] The invention also encompasses nucleic acid molecules which formtriple helical structures. For example, expression of a polypeptide ofthe invention can be inhibited by targeting nucleotide sequencescomplementary to the regulatory region of the gene encoding thepolypeptide (e.g., the promoter and/or enhancer) to form triple helicalstructures that prevent transcription of the gene in target cells. Seegenerally Helene (1991) Anticancer Drug Des. 6(6):569-84; Helene (1992)Ann. N. Y Acad. Sci. 660:27-36; and Maher (1992) Bioassays14(12):807-15.

[0581] In various embodiments, the nucleic acid molecules of theinvention can be modified at the base moiety, sugar moiety or phosphatebackbone to improve, e.g., the stability, hybridization, or solubilityof the molecule. For example, the deoxyribose phosphate backbone of thenucleic acids can be modified to generate peptide nucleic acids (seeHyrup et al. (1996) Bioorganic & Medicinal Chemistry 4(1): 5-23). Asused herein, the terms “peptide nucleic acids” or “PNAs” refer tonucleic acid mimics, e.g., DNA mimics, in which the deoxyribosephosphate backbone is replaced by a pseudopeptide backbone and only thefour natural nucleobases are retained. The neutral backbone of PNAs hasbeen shown to allow for specific hybridization to DNA and RNA underconditions of low ionic strength. The synthesis of PNA oligomers can beperformed using standard solid phase peptide synthesis protocols asdescribed in Hyrup et al. (1996), supra; Perry-O'Keefe et al. (1996)Proc. Natl. Acad. Sci. USA 93: 14670-675.

[0582] PNAs can be used in therapeutic and diagnostic applications. Forexample, PNAs can be used as antisense or antigene agents forsequence-specific modulation of gene expression by, e.g., inducingtranscription or translation arrest or inhibiting replication. PNAs canalso be used, e.g., in the analysis of single base pair mutations in agene by, e.g., PNA directed PCR clamping; as artificial restrictionenzymes when used in combination with other enzymes, e.g., S1 nucleases(Hyrup (1996), supra; or as probes or primers for DNA sequence andhybridization (Hyrup (1996), supra; Perry-O'Keefe et al. (1996) Proc.Natl. Acad. Sci. USA 93: 14670-675).

[0583] In another embodiment, PNAs can be modified, e.g., to enhancetheir stability or cellular uptake, by attaching lipophilic or otherhelper groups to PNA, by the formation of PNA-DNA chimeras, or by theuse of liposomes or other techniques of drug delivery known in the art.For example, PNA-DNA chimeras can be generated which may combine theadvantageous properties of PNA and DNA. Such chimeras allow DNArecognition enzymes, e.g., RNAse H and DNA polymerases, to interact withthe DNA portion while the PNA portion would provide high bindingaffinity and specificity. PNA-DNA chimeras can be linked using linkersof appropriate lengths selected in terms of base stacking, number ofbonds between the nucleobases, and orientation (Hyrup (1996), supra).The synthesis of PNA-DNA chimeras can be performed as described in Hyrup(1996), supra, and Finn et al. (1996) Nucleic Acids Res. 24(17):3357-63.For example, a DNA chain can be synthesized on a solid support usingstandard phosphoramidite coupling chemistry and modified nucleosideanalogs. Compounds such as 5′-(4-methoxytrityl)amino-5′-deoxy-thymidinephosphoramidite can be used as a link between the PNA and the 5′ end ofDNA (Mag et al. (1989) Nucleic Acids Res. 17:5973-88). PNA monomers arethen coupled in a stepwise manner to produce a chimeric molecule with a5′ PNA segment and a 3′ DNA segment (Finn et al. (1996) Nucleic AcidsRes. 24(17):3357-63). Alternatively, chimeric molecules can besynthesized with a 5′ DNA segment and a 3′ PNA segment (Peterser et al.(1975) Bioorganic Med. Chem. Lett. 5:1119-11124).

[0584] In other embodiments, the oligonucleotide may include otherappended groups such as peptides (e.g., for targeting host cellreceptors in vivo), or agents facilitating transport across the cellmembrane (see, e.g., Letsinger et al. (1989) Proc. NatL Acad. Sci. USA86:6553-6556; Lemaitre et al. (1987) Proc. Natl. Acad. Sci. USA84:648-652; PCT Publication No. WO 88/098 1 0) or the blood-brainbarrier (see, e.g., PCT Publication No. WO 89/10134). In addition,oligonucleotides can be modified with hybridization-triggered cleavageagents (see, e.g., Krol et al. (1988) Bio/Techniques 6:958-976) orintercalating agents (see, e.g., Zon (1988) Pharm. Res. 5:539-549). Tothis end, the oligonucleotide may be conjugated to another molecule,e.g., a peptide, hybridization triggered cross-linking agent, transportagent, hybridization-triggered cleavage agent, etc.

[0585] In still other embodiments, the nucleotides of the inventionincluding variants and derivatives can be used as vaccines, for exampleby genetic immunization. Genetic immunization is particularlyadvantageous as it stimulates a cytotoxic T-cell response but does notutilize live attenuated vaccines, which can revert to a virulent formand infect the host causing the very infection sought to be prevented.As used herein, genetic immunization comprises inserting the nucleotidesof the invention into a host, such that the nucleotides are taken up bycells of the host and the proteins encoded by the nucleotides aretranslated. These translated proteins are then either secreted orprocessed by the host cell for presentation to immune cells and animmune reaction is stimulated. Preferably, the immune reaction is acytotoxic T cell response, however, a humoral response or macrophagestimulation is also useful in preventing future infections. The skilledartisan will appreciate that there are various methods for introducingforeign nucleotides into a host animal and subsequently into cells forgenetic immunization, for example, by intramuscular injection of about50 mg of plasmid DNA encoding the proteins of the invention solubilizedin 50 ml of sterile saline solution, with a suitable adjuvant (Weinerand Kennedy (1999) Scientific American 7:50-57; Lowrie et al., (1999)Nature 400:269-271).

[0586] II. Isolated Proteins and Antibodies

[0587] One aspect of the invention pertains to isolated proteins, andbiologically active portions thereof, as well as polypeptide fragmentssuitable for use as immunogens to raise antibodies directed against apolypeptide of the invention. In one embodiment, the native polypeptidecan be isolated from cells or tissue sources by an appropriatepurification scheme using standard protein purification techniques. Inanother embodiment, polypeptides of the invention are produced byrecombinant DNA techniques. Alternative to recombinant expression, apolypeptide of the invention can be synthesized chemically usingstandard peptide synthesis techniques.

[0588] An “isolated” or “purified” protein or biologically activeportion thereof is substantially free of cellular material or othercontaminating proteins from the cell or tissue source from which theprotein is derived, or substantially free of chemical precursors orother chemicals when chemically synthesized. The language “substantiallyfree of cellular material” includes preparations of protein in which theprotein is separated from cellular components of the cells from which itis isolated or recombinantly produced. Thus, protein that issubstantially free of cellular material includes preparations of proteinhaving less than about 30%, 20%, 10%, or 5% (by dry weight) ofheterologous protein (also referred to herein as a “contaminatingprotein”). When the protein or biologically active portion thereof isrecombinantly produced, it is also preferably substantially free ofculture medium, i.e., culture medium represents less than about 20%,10%, or 5% of the volume of the protein preparation. When the protein isproduced by chemical synthesis, it is preferably substantially free ofchemical precursors or other chemicals, i.e., it is separated fromchemical precursors or other chemicals which are involved in thesynthesis of the protein. Accordingly such preparations of the proteinhave less than about 30%, 20%, 10%, 5% (by dry weight) of chemicalprecursors or compounds other than the polypeptide of interest.

[0589] Biologically active portions of a polypeptide of the inventioninclude polypeptides comprising amino acid sequences sufficientlyidentical to or derived from the amino acid sequence of the protein(e.g., the amino acid sequence shown in any of SEQ ID NO: 2, 4, 6, 8,10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, and44, which include fewer amino acids than the full length protein, andexhibit at least one activity of the corresponding full-length protein.Typically, biologically active portions comprise a domain or motif withat least one activity of the corresponding protein. A biologicallyactive portion of a protein of the invention can be a polypeptide whichis, for example, 10, 25, 50, 100 or more amino acids in length.Moreover, other biologically active portions, in which other regions ofthe protein are deleted, can be prepared by recombinant techniques andevaluated for one or more of the functional activities of the nativeform of a polypeptide of the invention.

[0590] Preferred polypeptides have the amino acid sequence of SEQ ID NO:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38,40, 42, and 44. Other useful proteins are substantially identical (e.g.,at least about 45%, preferably 55%, 65%, 75%, 85%, 95%, or 99%) to anyof SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30,32, 34, 36, 38, 40, 42, and 44, and retain the functional activity ofthe protein of the corresponding naturally-occurring protein yet differin amino acid sequence due to natural allelic variation or mutagenesis.

[0591] To determine the percent identity of two amino acid sequences orof two nucleic acids, the sequences are aligned for optimal comparisonpurposes (e.g., gaps can be introduced in the sequence of a first aminoacid or nucleic acid sequence for optimal alignment with a second aminoor nucleic acid sequence). The amino acid residues or nucleotides atcorresponding amino acid positions or nucleotide positions are thencompared. When a position in the first sequence is occupied by the sameamino acid residue or nucleotide as the corresponding position in thesecond sequence, then the molecules are identical at that position. Thepercent identity between the two sequences is a function of the numberof identical positions shared by the sequences (i.e., % identity=# ofidentical positions/total # of positions (e.g., overlappingpositions)×100). In one embodiment, the two sequences are the samelength.

[0592] The determination of percent identity between two sequences canbe accomplished using a mathematical algorithm. A preferred,non-limiting example of a mathematical algorithm utilized for thecomparison of two sequences is the algorithm of Karlin and Altschul(1990) Proc. Natl. Acad. Sci. USA 87:2264-2268, modified as in Karlinand Altschul (1993) Proc. Natl. Acad. Sci. USA 90:5873-5877. Such analgorithm is incorporated into the NBLAST and XBLAST programs ofAltschul, et al. (1990) J. Mol. Biol. 215:403-410. BLAST nucleotidesearches can be performed with the NBLAST program, score=100,wordlength=12 to obtain nucleotide sequences homologous to a nucleicacid molecules of the invention. BLAST protein searches can be performedwith the XBLAST program, score=50, wordlength=3 to obtain amino acidsequences homologous to a protein molecules of the invention. To obtaingapped alignments for comparison purposes, Gapped BLAST can be utilizedas described in Altschul et al. (1997) Nucleic Acids Res. 25:3389-3402.Alternatively, PSI-Blast can be used to perform an iterated search whichdetects distant relationships between molecules (Id.). When utilizingBLAST, Gapped BLAST, and PSI-Blast programs, the default parameters ofthe respective programs (e.g., XBLAST and NBLAST) can be used. Seehttp://www.ncbi.nlm.nih.gov.

[0593] Another preferred, non-limiting example of a mathematicalalgorithm utilized for the comparison of sequences is the algorithm ofMyers and Miller, (1988) CABIOS 4:11-17. Such an algorithm isincorporated into the ALIGN program (version 2.0) which is part of theGCG sequence alignment software package. When utilizing the ALIGNprogram for comparing amino acid sequences, a PAM120 weight residuetable, a gap length penalty of 12, and a gap penalty of 4 can be used.Additional algorithms for sequence analysis are known in the art andinclude ADVANCE and ADAM as described in Torellis and Robotti (1994)Comput. AppL. Biosci., 10:3-5; and FASTA described in Pearson and Lipman(1988) Proc. Natl. Acad. Sci. 85:2444-8. Within FASTA, ktup is a controloption that sets the sensitivity and speed of the search. If ktup=2,similar regions in the two sequences being compared are found by lookingat pairs of aligned residues; if ktup=1, single aligned amino acids areexamined. ktup can be set to 2 or 1 for protein sequences, or from 1 to6 for DNA sequences. The default if ktup is not specified is 2 forproteins and 6 for DNA. For a further description of FASTA parameters,see http://bioweb.pasteur.fr/docs/man/man/fasta.l.html#sect2, thecontents of which are incorporated herein by reference.

[0594] The percent identity between two sequences can be determinedusing techniques similar to those described above, with or withoutallowing gaps. In calculating percent identity, only exact matches arecounted.

[0595] The invention also provides chimeric or fusion proteins. As usedherein, a “chimeric protein” or “fusion protein” comprises all or part(preferably biologically active) of a polypeptide of the inventionoperably linked to a heterologous polypeptide (i.e., a polypeptide otherthan the same polypeptide of the invention). Within the fusion protein,the term “operably linked” is intended to indicate that the polypeptideof the invention and the heterologous polypeptide are fused in-frame toeach other. The heterologous polypeptide can be fused to the N-terminusor C-terninus of the polypeptide of the invention.

[0596] In another embodiment, the protein of the invention can beexpressed as a dimer of itself. In this embodiment, a first domain ofthe protein is fused in frame to the same domain by a linker region. Thelinker can be a short flexible segment of amino acids, for example GGPGGor GPPGG, or a longer segment as needed. Alternatively, the first domainof the protein can be fused to a second domain of the protein, which isdifferent than the first domain.

[0597] One useful fusion protein is a GST fusion protein in which thepolypeptide of the invention is fused to the C-terminus of GSTsequences. Such fusion proteins can facilitate the purification of arecombinant polypeptide of the invention.

[0598] In another embodiment, the fusion protein contains a heterologoussignal sequence at its N-terminus. For example, the native signalsequence of a polypeptide of the invention can be removed and replacedwith a signal sequence from another protein. For example, the gp67secretory sequence of the baculovirus envelope protein can be used as aheterologous signal sequence (Current Protocols in Molecular Biology,Ausubel et al., eds., John Wiley & Sons, 1992). Other examples ofeukaryotic heterologous signal sequences include the secretory sequencesof melittin and human placental alkaline phosphatase (Stratagene; LaJolla, Calif.). In yet another example, useful prokaryotic heterologoussignal sequences include the phoA secretory signal (Sambrook et al.,supra) and the protein A secretory signal (Pharmacia Biotech;Piscataway, N.J.).

[0599] In yet another embodiment, the fusion protein is animmunoglobulin fusion protein in which all or part of a polypeptide ofthe invention is fused with sequences derived from a member of theimmunoglobulin protein family. The immunoglobulin fusion proteins of theinvention can be incorporated into pharmaceutical compositions andadministered to a subject to inhibit an interaction between a ligand(soluble or membrane-bound) and a protein on the surface of a cell(receptor), to thereby suppress signal transduction in vivo. Theimmunoglobulin fusion protein can be used to affect the bioavailabilityof a cognate ligand of a polypeptide of the invention. Inhibition ofligand/receptor interaction can be useful therapeutically, both fortreating proliferative and differentiative disorders and for modulating(e.g., promoting or inhibiting) cell survival. Moreover, theimmunoglobulin fusion proteins of the invention can be used asimmunogens to produce antibodies directed against a polypeptide of theinvention in a subject, to purify ligands and in screening assays toidentify molecules which inhibit the interaction of receptors withligands. The immunoglobulin fusion protein can, for example, comprise aportion of a polypeptide of the invention fused with the amino-terminusor the carboxyl-terminus of an immunoglobulin constant region, asdisclosed in U.S. Pat. No. 5,714,147, U.S. Pat. No. 5,116,964, U.S. Pat.No. 5,514,582, and U.S. Pat. No. 5,455,165.

[0600] Chimeric and fusion proteins of the invention can be produced bystandard recombinant DNA techniques. In another embodiment, the fusiongene can be synthesized by conventional techniques including automatedDNA synthesizers. Alternatively, PCR amplification of gene fragments canbe carried out using anchor primers which give rise to complementaryoverhangs between two consecutive gene fragments which can subsequentlybe annealed and reamplified to generate a chimeric gene sequence (see,e.g., Ausubel et al., supra). Moreover, many expression vectors arecommercially available that already encode a fusion moiety (e.g., a GSTpolypeptide). A nucleic acid encoding a polypeptide of the invention canbe cloned into such an expression vector such that the fusion moiety islinked in-frame to the polypeptide of the invention.

[0601] A signal sequence of a polypeptide of the invention SEQ ID NO:14, 34 or 78 can be used to facilitate secretion and isolation of thesecreted protein or other proteins of interest. Signal sequences aretypically characterized by a core of hydrophobic amino acids which aregenerally cleaved from the mature protein during secretion in one ormore cleavage events. Such signal peptides contain processing sites thatallow cleavage of the signal sequence from the mature proteins as theypass through the secretory pathway. Thus, the invention pertains to thedescribed polypeptides having a signal sequence, as well as to thesignal sequence itself and to the polypeptide in the absence of thesignal sequence (i.e., the cleavage products). In one embodiment, anucleic acid sequence encoding a signal sequence of the invention can beoperably linked in an expression vector to a protein of interest, suchas a protein which is ordinarily not secreted or is otherwise difficultto isolate. The signal sequence directs secretion of the protein, suchas from a eukaryotic host into which the expression vector istransformed, and the signal sequence is subsequently or concurrentlycleaved. The protein can then be readily purified from the extracellularmedium by art recognized methods. Alternatively, the signal sequence canbe linked to the protein of interest using a sequence which facilitatespurification, such as with a GST domain.

[0602] In another embodiment, the signal sequences of the presentinvention can be used to identify regulatory sequences, e.g., promoters,enhancers, repressors. Since signal sequences are the mostamino-terminal sequences of a peptide, it is expected that the nucleicacids which flank the signal sequence on its amino-terminal side will beregulatory sequences which affect transcription. Thus, a nucleotidesequence which encodes all or a portion of a signal sequence can be usedas a probe to identify and isolate signal sequences and their flankingregions, and these flanking regions can be studied to identifyregulatory elements therein.

[0603] The present invention also pertains to variants of thepolypeptides of the invention. Such variants have an altered amino acidsequence which can function as either agonists (mimetics) or asantagonists. Variants can be generated by mutagenesis, e.g., discretepoint mutation or truncation. An agonist can retain substantially thesame, or a subset, of the biological activities of the naturallyoccurring form of the protein. An antagonist of a protein can inhibitone or more of the activities of the naturally occurring form of theprotein by, for example, competitively binding to a downstream orupstream member of a cellular signaling cascade which includes theprotein of interest. Thus, specific biological effects can be elicitedby treatment with a variant of limited function. Treatment of a subjectwith a variant having a subset of the biological activities of thenaturally occurring form of the protein can have fewer side effects in asubject relative to treatment with the naturally occurring form of theprotein.

[0604] Variants of a protein of the invention which function as eitheragonists (mimetics) or as antagonists can be identified by screeningcombinatorial libraries of mutants, e.g., truncation mutants, of theprotein of the invention for agonist or antagonist activity. In oneembodiment, a variegated library of variants is generated bycombinatorial mutagenesis at the nucleic acid level and is encoded by avariegated gene library. A variegated library of variants can beproduced by, for example, enzymatically ligating a mixture of syntheticoligonucleotides into gene sequences such that a degenerate set ofpotential protein sequences is expressible as individual polypeptides,or alternatively, as a set of larger fusion proteins (e.g., for phagedisplay). There are a variety of methods which can be used to producelibraries of potential variants of the polypeptides of the inventionfrom a degenerate oligonucleotide sequence. Methods for synthesizingdegenerate oligonucleotides are known in the art (see, e.g., Narang(1983) Tetrahedron 39:3; Itakura et al. (1984) Annu. Rev. Biochem.53:323; Itakura et al. (1984) Science 198:1056; Ike et al. (1983)Nucleic Acid Res. 11:477).

[0605] In addition, libraries of fragments of the coding sequence of apolypeptide of the invention can be used to generate a variegatedpopulation of polypeptides for screening and subsequent selection ofvariants. For example, a library of coding sequence fragments can begenerated by treating a double stranded PCR fragment of the codingsequence of interest with a nuclease under conditions wherein nickingoccurs only about once per molecule, denaturing the double stranded DNA,renaturing the DNA to form double stranded DNA which can includesense/antisense pairs from different nicked products, removing singlestranded portions from reformed duplexes by treatment with S1 nuclease,and ligating the resulting fragment library into an expression vector.By this method, an expression library can be derived which encodesN-terminal and internal fragments of various sizes of the protein ofinterest.

[0606] Several techniques are known in the art for screening geneproducts of combinatorial libraries made by point mutations ortruncation, and for screening cDNA libraries for gene products having aselected property. The most widely used techniques, which are amenableto high through-put analysis, for screening large gene librariestypically include cloning the gene library into replicable expressionvectors, transforming appropriate cells with the resulting library ofvectors, and expressing the combinatorial genes under conditions inwhich detection of a desired activity facilitates isolation of thevector encoding the gene whose product was detected. Recursive ensemblemutagenesis (REM), a technique which enhances the frequency offunctional mutants in the libraries, can be used in combination with thescreening assays to identify variants of a protein of the invention(Arkin and Yourvan (1992) Proc. Natl. Acad. Sci. USA 89:7811-7815;Delgrave et al. (1993) Protein Engineering 6(3):327-331).

[0607] The polypeptides of the invention can exhibit post-translationalmodifications, including, but not limited to glycosylations, (e.g.,N-linked or O-linked glycosylations), myristylations, palmitylations,acetylations and phosphorylations (e.g., serine/threonine or tyrosine).In one embodiment, the polypeptides of the invention exhibit reducedlevels of O-linked glycosylation and/or N-linked glycosylation relativeto endogenously expressed TANGO 239, TANGO 219, TANGO 232, TANGO 281,A236 (INTERCEPT 236), TANGO 300, TANGO 353, TANGO 393, TANGO 402, TANGO351 and TANGO 509 polypeptides. In another embodiment, the polypeptidesof the invention do not exhibit O-linked glycosylation or N-linkedglycosylation.

[0608] The polypeptides of the invention can, for example, includemodifications that can increase such attributes as stability, half-life,ability to enter cells and aid in administration, e.g., in vivoadministration of the polypeptides of the invention. For example,polypeptides of the invention can comprise a protein transduction domainof the HIV TAT protein as described in Schwarze, et al. (1999 Science285:1569-1572), thereby facilitating delivery of polypeptides of theinvention into cells.

[0609] An isolated polypeptide of the invention, or a fragment thereof,can be used as an immunogen to generate antibodies using standardtechniques for polyclonal and monoclonal antibody preparation. Thefull-length polypeptide or protein can be used or, alternatively, theinvention provides antigenic peptide fragments for use as immunogens.The antigenic peptide of a protein of the invention comprises at least 8(preferably 10, 15, 20, or 30) amino acid residues of the amino acidsequence of SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26,28, 30, 32, 34, 36, 38, 40, 42, and 44, and encompasses an epitope ofthe protein such that an antibody raised against the peptide forms aspecific immune complex with the protein.

[0610] Preferred epitopes encompassed by the antigenic peptide areregions that are located on the surface of the protein, e.g.,hydrophilic regions. FIGS. 2, 8, 20, and 23 and are hydropathy plots ofthe proteins of the invention. These plots or similar analyses can beused to identify hydrophilic regions. In certain embodiments, thenucleic acid molecules of the invention are present as part of nucleicacid molecules comprising nucleic acid sequences that contain or encodeheterologous (e.g., vector, expression vector, or fusion protein)sequences. These nucleotides can then be used to express proteins whichcan be used as immunogens to generate an immune response, or moreparticularly, to generate polyclonal or monoclonal antibodies specificto the expressed protein.

[0611] An immunogen typically is used to prepare antibodies byimmunizing a suitable subject, (e.g., rabbit, goat, mouse or othermammal). An appropriate immunogenic preparation can contain, forexample, recombinantly expressed or chemically synthesized polypeptide.The preparation can further include an adjuvant, such as Freund'scomplete or incomplete adjuvant, or similar immunostimulatory agent.

[0612] Accordingly, another aspect of the invention pertains toantibodies directed against a polypeptide of the invention. The term“antibody” as used herein refers to immunoglobulin molecules andimmunologically active portions of immunoglobulin molecules, i.e.,molecules that contain an antigen binding site which specifically bindsan antigen, such as a polypeptide of the invention, e.g., an epitope ofa polypeptide of the invention. A molecule which specifically binds to agiven polypeptide of the invention is a molecule which binds thepolypeptide, but does not substantially bind other molecules in asample, e.g., a biological sample, which naturally contains thepolypeptide. Examples of immunologically active portions ofimmunoglobulin molecules include F(ab) and F(ab′)₂ fragments which canbe generated by treating the antibody with an enzyme such as pepsin. Theinvention provides polyclonal and monoclonal antibodies. The term“monoclonal antibody” or “monoclonal antibody composition”, as usedherein, refers to a population of antibody molecules that contain onlyone species of an antigen binding site capable of immunoreacting with aparticular epitope.

[0613] Polyclonal antibodies can be prepared as described above byimmunizing a suitable subject with a polypeptide of the invention as animmunogen. Preferred polyclonal antibody compositions are ones that havebeen selected for antibodies directed against a polypeptide orpolypeptides of the invention. Particularly preferred polygonal antibodypreparations are ones that contain only antibodies directed against apolypeptide or polypeptides of the invention. Particularly preferredimmunogen compositions are those that contain no other human proteinssuch as, for example, immunogen compositions made using a non-human hostcell for recombinant expression of a polypeptide of the invention. Insuch a manner, the only human epitope or epitopes recognized by theresulting antibody compositions raised against this immunogen will bepresent as part of a polypeptide or polypeptides of the invention.

[0614] The antibody titer in the immunized subject can be monitored overtime by standard techniques, such as with an enzyme linked immunosorbentassay (ELISA) using immobilized polypeptide. If desired, the antibodymolecules can be isolated from the mammal (e.g., from the blood) andfurther purified by well-known techniques, such as protein Achromatography to obtain the IgG fraction. Alternatively, antibodiesspecific for a protein or polypeptide of the invention can be selectedfor (e.g., partially purified) or purified by, e.g., affinitychromatography. For example, a recombinantly expressed and purified (orpartially purified) protein of the invention is produced as describedherein, and covalently or non-covalently coupled to a solid support suchas, for example, a chromatography column. The column can then be used toaffinity purify antibodies specific for the proteins of the inventionfrom a sample containing antibodies directed against a large number ofdifferent epitopes, thereby generating a substantially purified antibodycomposition, i.e., one that is substantially free of contaminatingantibodies. By a substantially purified antibody composition is meant,in this context, that the antibody sample contains at most only 30% (bydry weight) of contaminating antibodies directed against epitopes otherthan those on the desired protein or polypeptide of the invention, andpreferably at most 20%, yet more preferably at most 10%, and mostpreferably at most 5% (by dry weight) of the sample is contaminatingantibodies. A purified antibody composition means that at least 99% ofthe antibodies in the composition are directed against the desiredprotein or polypeptide of the invention.

[0615] At an appropriate time after immunization, e.g., when thespecific antibody titers are highest, antibody-producing cells can beobtained from the subject and used to prepare monoclonal antibodies bystandard techniques, such as the hybridoma technique originallydescribed by Kohler and Milstein (1975) Nature 256:495-497, the human Bcell hybridoma technique (Kozbor et al. (1983) Immunol. Today 4:72), theEBV-hybridoma technique (Cole et al. (1985), Monoclonal Antibodies andCancer Therapy, Alan R. Liss, Inc., pp. 77-96) or trioma techniques. Thetechnology for producing hybridomas is well known (see generally CurrentProtocols in Immunology (1994) Coligan et al. (eds.) John Wiley & Sons,Inc., New York, N.Y.). Hybridoma cells producing a monoclonal antibodyof the invention are detected by screening the hybridoma culturesupernatants for antibodies that bind the polypeptide of interest, e.g.,using a standard ELISA assay.

[0616] Alternative to preparing monoclonal antibody-secretinghybridomas, a monoclonal antibody directed against a polypeptide of theinvention can be identified and isolated by screening a recombinantcombinatorial immunoglobulin library (e.g., an antibody phage displaylibrary) with the polypeptide of interest. Kits for generating andscreening phage display libraries are commercially available (e.g., thePharnacia Recombinant Phage Antibody System, Catalog No. 27-9400-01; andthe Stratagene SurfZAP Phage Display Kit, Catalog No. 240612).Additionally, examples of methods and reagents particularly amenable foruse in generating and screening antibody display library can be foundin, for example, U.S. Pat. No. 5,223,409; PCT Publication No. WO92/18619; PCT Publication No. WO 91/17271; PCT Publication No. WO92/20791; PCT Publication No. WO 92/15679; PCT Publication No. WO93/01288; PCT Publication No. WO 92/01047; PCT Publication No. WO92/09690; PCT Publication No. WO 90/02809; Fuchs et al. (1991)Bio/Technology 9:1370-1372; Hay et al. (1992) Hum. Antibod. Hybridomas3:81-85; Huse et al. (1989) Science 246:1275-1281; Griffiths et al.(1993) EMBO J. 12:725-734.

[0617] Additionally, recombinant antibodies, such as chimeric andhumanized monoclonal antibodies, comprising both human and non-humanportions, which can be made using standard recombinant DNA techniques,are within the scope of the invention. A chimeric antibody is a moleculein which different portions are derived from different animal species,such as those having a variable region derived from a murine mAb and ahuman immunoglobulin constant region. (See, e.g., Cabilly et al., U.S.Pat. No. 4,816,567; and Boss et al., U.S. Pat. No. 4,816,397, which areincorporated herein by reference in their entirety.) Humanizedantibodies are antibody molecules from non-human species having one ormore complementarily determining regions (CDRs) from the non-humanspecies and a framework region from a human immunoglobulin molecule.(See, e.g., Queen, U.S. Pat. No. 5,585,089, which is incorporated hereinby reference in its entirety.) Such chimeric and humanized monoclonalantibodies can be produced by recombinant DNA techniques known in theart, for example using methods described in PCT Publication No. WO87/02671; European patent application 184,187; European patentapplication 171,496; European patent application 173,494; PCTPublication No. WO 86/01533; U.S. Pat. No. 4,816,567; European patentapplication 125,023; Better et al. (1988) Science 240:1041-1043; Liu etal. (1987) Proc. Natl. Acad. Sci. USA 84:3439-3443; Liu et al. (1987) J.Immunol. 139:3521-3526; Sun et al. (1987) Proc. Natl. Acad. Sci. USA84:214-218; Nishimura et al. (1987) Canc. Res. 47:999-1005; Wood et al.(1985) Nature 314:446-449; and Shaw et al. (1988) J. Natl. Cancer Inst.80:1553-1559); Morrison (1985) Science 229:1202-1207; Oi et al. (1986)Bio/Techniques 4:214; U.S. Pat. No. 5,225,539; Jones et al. (1986)Nature 321:552-525; Verhoeyan et al. (1988) Science 239:1534; andBeidler et al. (1988) J. Immunol. 141:4053-4060.

[0618] Completely human antibodies are particularly desirable fortherapeutic treatment of human patients. Such antibodies can beproduced, for example, using transgenic mice which are incapable ofexpressing endogenous immunoglobulin heavy and light chains genes, butwhich can express human heavy and light chain genes. The transgenic miceare immunized in the normal fashion with a selected antigen, e.g., allor a portion of a polypeptide of the invention. Monoclonal antibodiesdirected against the antigen can be obtained using conventionalhybridoma technology. The human immunoglobulin transgenes harbored bythe transgenic mice rearrange during B cell differentiation, andsubsequently undergo class switching and somatic mutation. Thus, usingsuch a technique, it is possible to produce therapeutically useful IgG,IgA and IgE antibodies. For an overview of this technology for producinghuman antibodies, see Lonberg and Huszar (1995, Int. Rev. Immunol.13:65-93). For a detailed discussion of this technology for producinghuman antibodies and human monoclonal antibodies and protocols forproducing such antibodies, see, e.g., U.S. Pat. No. 5,625,126; U.S. Pat.No. 5,633,425; U.S. Pat. No. 5,569,825; U.S. Pat. No. 5,661,016; andU.S. Pat. No. 5,545,806. In addition, companies such as Abgenix, Inc.(Freemont, Calif.), can be engaged to provide human antibodies directedagainst a selected antigen using technology similar to that describedabove.

[0619] Completely human antibodies which recognize a selected epitopecan be generated using a technique referred to as “guided selection.” Inthis approach a selected non-human monoclonal antibody, e.g., a mouseantibody, is used to guide the selection of a completely human antibodyrecognizing the same epitope. (Jespers et al. (1994) Bio/technology12:899-903).

[0620] An antibody directed against a polypeptide of the invention(e.g., monoclonal antibody) can be used to isolate the polypeptide bystandard techniques, such as affinity chromatography orimmunoprecipitation. Moreover, such an antibody can be used to detectthe protein (e.g., in a cellular lysate or cell supernatant) in order toevaluate the abundance and pattern of expression of the polypeptide. Theantibodies can also be used diagnostically to monitor protein levels intissue as part of a clinical testing procedure, e.g., to, for example,determine the efficacy of a given treatment regimen. Detection can befacilitated by coupling the antibody to a detectable substance. Examplesof detectable substances include various enzymes, prosthetic groups,fluorescent materials, luminescent materials, bioluminescent materials,and radioactive materials. Examples of suitable enzymes includehorseradish peroxidase, alkaline phosphatase, beta-galactosidase, oracetylcholinesterase; examples of suitable prosthetic group complexesinclude streptavidin/biotin and avidin/biotin; examples of suitablefluorescent materials include umbelliferone, fluorescein, fluoresceinisothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansylchloride or phycoerythrin; an example of a luminescent material includesluminol; examples of bioluminescent materials include luciferase,luciferin, and aequorin, and examples of suitable radioactive materialinclude ¹²⁵I, ¹³¹I, ³⁵S or ³H.

[0621] In addition, the TANGO 239, TANGO 219, TANGO 232, TANGO 281, A236(INTERCEPT 236), TANGO 300, TANGO 353, TANGO 393, TANGO 402, TANGO 351and TANGO 509 gene sequences and gene products, including peptidefragments and fusion proteins thereof, and antibodies directed againstsaid gene products and peptide fragments thereof, have applications forpurposes independent of the role of the gene products, as describedabove. For example, gene products of the invention, including peptidefragments, as well as specific antibodies thereto, can be used forconstruction of fusion proteins to facilitate recovery, detection, orlocalization of another protein of interest. In addition, genes and geneproducts of the invention can be used for genetic mapping. Finally,TANGO 239, TANGO 219, TANGO 232, TANGO 281, A236 (INTERCEPT 236), TANGO300, TANGO 353, TANGO 393, TANGO 402, TANGO 351 and TANGO 509 nucleicacids and gene products have generic uses, such as supplemental sourcesof nucleic acids, proteins and amino acids for food additives orcosmetic products.

[0622] Further, an antibody (or fragment thereof) may be conjugated to atherapeutic moiety such as a cytotoxin, a therapeutic agent or aradioactive metal ion. A cytotoxin or cytotoxic agent includes any agentthat is detrimental to cells. Examples include taxol, cytochalasin B,gramicidin D, ethidium bromide, emetine, mitomycin, etoposide,tenoposide, vincristine, vinblastine, colchicin, doxorubicin,daunorubicin, dihydroxy anthracin dione, mitoxantrone, mithramycin,actinomycin D, 1-dehydrotestosterone, glucocorticoids, procaine,tetracaine, lidocaine, propranolol, and puromycin and analogs orhomologs thereof. Therapeutic agents include, but are not limited to,antimetabolites (e.g., methotrexate, 6-mercaptopurine, 6-thioguanine,cytarabine, 5-fluorouracil decarbazine), alkylating agents (e.g.,mechlorethamine, thioepa chlorambucil, melphalan, carmustine (BSNU) andlomustine (CCNU), cyclothosphamide, busulfan, dibromomannitol,streptozotocin, mitomycin C, and cis-dichlorodiamine platinum (II) (DDP)cisplatin), anthracyclines (e.g., daunorubicin (formerly daunomycin) anddoxorubicin), antibiotics (e.g., dactinomycin (formerly actinomycin),bleomycin, mithramycin, and anthramycin (AMC)), and anti-mitotic agents(e.g., vincristine and vinblastine).

[0623] The conjugates of the invention can be used for modifying a givenbiological response, the drug moiety is not to be construed as limitedto classical chemical therapeutic agents. For example, the drug moietymay be a protein or polypeptide possessing a desired biologicalactivity. Such proteins may include, for example, a toxin such as abrin,ricin A, pseudomonas exotoxin, or diphtheria toxin; a protein such astumor necrosis factor, α-interferon, β-interferon, nerve growth factor,platelet derived growth factor, tissue plasminogen activator, athrombotic agent or an anti-angiogenic agent, e.g., angiostatin orendostatin; or, biological response modifiers such as, for example,lymphokines, interleukin-1 (“IL-1”), interleukin-2 (“IL-2”),interleukin-4 (“IL-4”), interleukin-6 (“IL-6”), interleukin-7 (“IL-7”),granulocyte macrophase colony stimulating factor (“GM-CSF”), granulocytecolony stimulating factor (“G-CSF”), interleukin-10 (“IL-10”),interleukin-12 (“IL-12”), interleukin-1 5 (“IL-15”), interferon-γ(“IFN-γ”), interferon-α (“IFN-α”), or other immune factors or growthfactors.

[0624] Techniques for conjugating such therapeutic moiety to antibodiesare well known, see, e.g., Armon et al., “Monoclonal Antibodies Forhimunotargeting Of Drugs In Cancer Therapy”, in Monoclonal AntibodiesAnd Cancer Therapy, Reisfeld et al. (eds.), pp. 243-56 (Alan R. Liss,Inc. 1985); Hellstrom et al., “Antibodies For Drug Delivery”, inControlled Drug Delivery (2nd Ed.), Robinson et al. (eds.), pp. 623-53(Marcel Dekker, Inc. 1987); Thorpe, “Antibody Carriers Of CytotoxicAgents In Cancer Therapy: A Review”, in Monoclonal Antibodies '84:Biological And Clinical applications, Pinchera et al. (eds.), pp.475-506 (1985); “Analysis, Results, And Future Prospective Of TheTherapeutic Use Of Radiolabeled Antibody In Cancer Therapy”, inMonoclonal Antibodies For Cancer Detection And Therapy, Baldwin et al.(eds.), pp. 303-16 (Academic Press 1985), and Thorpe et al., “ThePreparation And Cytotoxic Properties Of Antibody-Toxin Conjugates”,Immunol. Rev., 62:119-58 (1982).

[0625] Alternatively, an antibody can be conjugated to a second antibodyto form an antibody heteroconjugate as described by Segal in U.S. Pat.No. 4,676,980.

[0626] An antibody with or without a therapeutic moiety conjugated to itcan be used as a therapeutic that is administered alone or incombination with chemotherapeutic agents.

[0627] Alternatively, an antibody of the invention can be conjugated toa second antibody to form an “antibody heteroconjugate” as described bySegal in U.S. Pat. No. 4,676,980 or alternatively, two antibodies can beconjugated to each other to create a bispecific heteromers, or an“antibody heteropolymer” as described in Taylor et al., in U.S. Pat.Nos. 5,470,570 and 5,487,890.

[0628] An antibody with or without a therapeutic moiety conjugated to itcan be used as a therapeutic that is administered alone or incombination with cytotoxic factor(s) and/or cytokine(s).

[0629] In yet a further aspect, the invention provides substantiallypurified antibodies or fragments thereof, including human or non-humanantibodies or fragments thereof, which antibodies or fragmentsspecifically bind to a polypeptide of the invention comprising an aminoacid sequence selected from the group consisting of: the amino acidsequence of SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26,28, 30, 32, 34, 36, 38, 40, 42, or 44, or the amino acid sequenceencoded by the CDNA insert of the plasmid deposited on Oct. 1, 1999 withthe ATCC® and having the deposit number 98999, 98899, 207045, 207046,207222, PTA-34, PTA-34, PTA-224, PTA-293, PTA-292, PTA-295, PTA-294,PTA-424, and PTA-438; a fragment of at least 15 contiguous amino acidresidues of the amino acid sequence of SEQ ID NOs: 2, 4, 6, 8, 10, 12,14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, or 44 or theamino acid sequence encoded by the CDNA insert of the plasmid depositedwith the ATCC® deposit number 98999, 98899, 207045, 207046, 207222,PTA-34, PTA-34, PTA-224, PTA-293, PTA-292, PTA-295, PTA-294, PTA-424,and PTA-438; an amino acid sequence which is at least 95% identical tothe amino acid sequence of SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18,20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, or 44 or the amino acidsequence encoded by the CDNA insert of the plasmid deposited with theATCC® deposit number 98999, 98899, 207045, 207046, 207222, PTA-34,PTA-34, PTA-224, PTA-293, PTA-292, PTA-295, PTA-294, PTA-424, andPTA-438, wherein the percent identity is determined using the ALIGNprogram of the GCG software package with a PAM120 weight residue table,a gap length penalty of 12, and a gap penalty of 4; and an amino acidsequence which is encoded by a nucleic acid molecule which hybridizes tothe nucleic acid molecule consisting of SEQ ID NOs: 1, 3, 5, 7, 9, 11,13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43 or to thecDNA insert of the plasmid deposited with the ATCC® deposit number98999, 98899, 207045, 207046, 207222, PTA-34, PTA-34, PTA-224, PTA-293,PTA-292, PTA-295, PTA-294, PTA-424, and PTA-438, under conditions ofhybridization of 6×SSC at 45° C. and washing in 0.2×SSC, 0.1% SDS at 65°C. In various embodiments, the substantially purified antibodies of theinvention, or fragments thereof, can be human, non-human, chimericand/or humanized antibodies.

[0630] In another aspect, the invention provides human or non-humanantibodies or fragments thereof, which antibodies or fragmentsspecifically bind to a polypeptide comprising an amino acid sequenceselected from the group consisting of: the amino acid sequence of SEQ IDNOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36,38, 40, 42, or 44 or the amino acid sequence encoded by the cDNA insertof the plasmid deposited with the ATCC® deposit number 98999, 98899,207045, 207046, 207222, PTA-34, PTA-34, PTA-224, PTA-293, PTA-292,PTA-295, PTA-294, PTA-424, and PTA-438; a fragment of at least 15contiguous amino acid residues of the amino acid sequence of SEQ ID NOs:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38,40, 42, or 44 or the amino acid sequence encoded by the cDNA insert ofthe plasmid deposited with the ATCC® deposit number 98999, 98899,207045, 207046, 207222, PTA-34, PTA-34, PTA-224, PTA-293, PTA-292,PTA-295, PTA-294, PTA-424, and PTA-438; an amino acid sequence which isat least 95% identical to the amino acid sequence of SEQ ID NOs: 2, 4,6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40,42, or 44 or the amino acid sequence encoded by the cDNA insert of theplasmid deposited with the ATCC® deposit number 98999, 98899, 207045,207046, 207222, PTA-34, PTA-34, PTA-224, PTA-293, PTA-292, PTA-295,PTA-294, PTA-424, and PTA-438, wherein the percent identity isdetermined using the ALIGN program of the GCG software package with aPAM120 weight residue table, a gap length penalty of 12, and a gappenalty of 4; and an amino acid sequence which is encoded by a nucleicacid molecule which hybridizes to the nucleic acid molecule consistingof SEQ ID NOs: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29,31, 33, 35, 37, 39, 41, 43 or to the cDNA insert of the plasmiddeposited with the ATCC® deposit number 98999, 98899, 207045, 207046,207222, PTA-34, PTA-34, PTA-224, PTA-293, PTA-292, PTA-295, PTA-294,PTA-424, and PTA-438, under conditions of hybridization of 6×SSC at 45°C. and washing in 0.2×SSC, 0.1% SDS at 65° C. Such non-human antibodiescan be goat, mouse, sheep, horse, chicken, rabbit, or rat antibodies.Alternatively, the non-human antibodies of the invention can be chimericand/or humanized antibodies. In addition, the non-human antibodies ofthe invention can be polyclonal antibodies or monoclonal antibodies.

[0631] In still a further aspect, the invention provides monoclonalantibodies or fragments thereof, which antibodies or fragmentsspecifically bind to a polypeptide of the invention comprising an aminoacid sequence selected from the group consisting of: the amino acidsequence of SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26,28, 30, 32, 34, 36, 1 0 38, 40, 42, or 44 or the amino acid sequenceencoded by the cDNA insert of the plasmid deposited with the ATCC®deposit number 98999, 98899, 207045, 207046, 207222, PTA-34, PTA-34,PTA-224, PTA-293, PTA-292, PTA-295, PTA-294, PTA-424, and PTA-438; afragment of at least 15 contiguous amino acid residues of the amino acidsequence of SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26,28, 30, 32, 34, 36, 15 38, 40, 42, or 44 or the amino acid sequenceencoded by the cDNA insert of the plasmid deposited with the ATCC®deposit number 98999, 98899, 207045, 207046, 207222, PTA-34, PTA-34,PTA-224, PTA-293, PTA-292, PTA-295, PTA-294, PTA-424, and PTA-438; anamino acid sequence which is at least 95% identical to the amino acidsequence of SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26,28, 30, 32, 34, 36, 38, 40, 42, or 44 or the amino acid sequence encodedby the cDNA insert of the plasmid deposited with the ATCC® depositnumber 98999, 98899, 207045, 207046, 207222, PTA-34, PTA-34, PTA-224,PTA-293, PTA-292, PTA-295, PTA-294, PTA-424, and PTA-438, wherein thepercent identity is determined using the ALIGN program of the GCGsoftware package with a PAM120 weight residue table, a gap lengthpenalty of 12, and a gap penalty of 4; and an amino acid sequence whichis encoded by a nucleic acid molecule which hybridizes to the nucleicacid molecule consisting of SEQ ID NOs: 1, 3, 5, 7, 9, 11, 13, 15, 17,19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43 or the cDNA insert ofthe plasmid deposited with the ATCC® deposit number 98999, 98899,207045, 207046, 207222, PTA-34, PTA-34, PTA-224, PTA-293, PTA-292,PTA-295, PTA-294, PTA-424, and PTA-438, under conditions ofhybridization of 6×SSC at 45° C. and washing in 0.2×SSC, 0.1% SDS at 65°C. The monoclonal antibodies can be human, humanized, chimeric and/ornon-human antibodies.

[0632] The substantially purified antibodies or fragments thereofspecifically bind to a signal peptide, a secreted sequence, anextracellular domain, a transmembrane or a cytoplasmic domaincytoplasmic membrane of a polypeptide of the invention. In aparticularly preferred embodiment, the substantially purified antibodiesor fragments thereof, the non-human antibodies or fragments thereof,and/or the monoclonal antibodies or fragments thereof, of the inventionspecifically bind to a secreted sequence, or alternatively, to anextracellular domain of the amino acid sequence of the invention.

[0633] Examples of preferred epitopes, i.e., epitopes in extracellulardomains of polypeptides of the invention, can be identified usinghydropathy plots as shown in FIGS: 2, 7, 10, 18, 21, 24, 29, 31, 33, 37,39, 41, 45, 49, 51 and 54.

[0634] Any of the antibodies of the invention can be conjugated to atherapeutic moiety or to a detectable substance. Non-limiting examplesof detectable substances that can be conjugated to the antibodies of theinvention are an enzyme, a prosthetic group, a fluorescent material, aluminescent material, a bioluminescent material, and a radioactivematerial.

[0635] The invention also provides a kit containing an antibody of theinvention conjugated to a detectable substance, and instructions foruse. Still another aspect of the invention is a pharmaceuticalcomposition comprising an antibody of the invention and apharmaceutically acceptable carrier. In preferred embodiments, thepharmaceutical composition contains an antibody of the invention, atherapeutic moiety, and a pharmaceutically acceptable carrier.

[0636] Still another aspect of the invention is a method of making anantibody that specifically recognizes TANGO 239, TANGO 219, TANGO 232,TANGO 281, A236 (INTERCEPT 236), TANGO 300, TANGO 353, TANGO 393, TANGO402, TANGO 351 and TANGO 509, the method comprising immunizing a mammalwith a polypeptide. The polypeptide used as an immunogen comprises anamino acid sequence selected from the group consisting of: the aminoacid sequence of any one of SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18,20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, or 44 or an amino acidsequence encoded by the cDNA of a clone deposited as ATCC® depositnumber 98999, 98899, 207045, 207046, 207222, PTA-34, PTA-34, PTA-224,PTA-293, PTA-292, PTA-295, PTA-294, PTA-424, and PTA-438; a fragment ofat least 15 contiguous amino acid residues of the amino acid sequence ofany one of SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26,28, 30, 32, 34, 36, 38, 40, 42, or 44 an amino acid sequence which is atleast 95% identical to the amino acid sequence of any one of SEQ ID NOs:2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38,40, 42, or 44 wherein the percent identity is determined using the ALIGNprogram of the GCG software package with a PAM120 weight residue table,a gap length penalty of 12, and a gap penalty of 4; and an amino acidsequence which is encoded by a nucleic acid molecule which hybridizes tothe nucleic acid molecule consisting of any one of SEQ ID NOs: 1, 3, 5,7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, or43, or the cDNA of a clone deposited as ATCC® deposit number 98999,98899, 207045, 207046, 207222, PTA-34, PTA-34, PTA-224, PTA-293,PTA-292, PTA-295, PTA-294, PTA-424, and PTA-438, or a complementthereof, under conditions of hybridization of 6×SSC at 45° C. andwashing in 0.2×SSC, 0.1% SDS at 65° C. After immunization, a sample iscollected from the mammal that contains an antibody that specificallyrecognizes the immunogen. Preferably, the polypeptide is recombinantlyproduced using a non-human host cell. Optionally, the antibodies can befurther purified from the sample using techniques well known to those ofskill in the art. The method can further comprise producing a monoclonalantibody-producing cell from the cells of the mammal. Optionally,antibodies are collected from the antibody-producing cell.

[0637] III. Recombinant Expression Vectors and Host Cells

[0638] Another aspect of the invention pertains to vectors, preferablyexpression vectors, containing a nucleic acid encoding a polypeptide ofthe invention (or a portion thereof). As used herein, the term “vector”refers to a nucleic acid molecule capable of transporting anothernucleic acid to which it has been linked. One type of vector is a“plasmid”, which refers to a circular double stranded DNA loop intowhich additional DNA segments can be ligated. Another type of vector isa viral vector, wherein additional DNA segments can be ligated into theviral genome. Certain vectors are capable of autonomous replication in ahost cell into which they are introduced (e.g., bacterial vectors havinga bacterial origin of replication and episomal mammalian vectors). Othervectors (e.g., non-episomal mammalian vectors) are integrated into thegenome of a host cell upon introduction into the host cell, and therebyare replicated along with the host genome. Moreover, certain vectors,expression vectors, are capable of directing the expression of genes towhich they are operably linked. In general, expression vectors ofutility in recombinant DNA techniques are often in the form of plasmids(vectors). However, the invention is intended to include such otherforms of expression vectors, such as viral vectors (e.g., replicationdefective retroviruses, adenoviruses and adeno-associated viruses),which serve equivalent functions.

[0639] The recombinant expression vectors of the invention comprise anucleic acid of the invention in a form suitable for expression of thenucleic acid in a host cell. This means that the recombinant expressionvectors include one or more regulatory sequences, selected on the basisof the host cells to be used for expression, which is operably linked tothe nucleic acid sequence to be expressed. Within a recombinantexpression vector, “operably linked” is intended to mean that thenucleotide sequence of interest is linked to the regulatory sequence(s)in a manner which allows for expression of the nucleotide sequence(e.g., in an in vitro transcription/translation system or in a host cellwhen the vector is introduced into the host cell). The term “regulatorysequence” is intended to include promoters, enhancers and otherexpression control elements (e.g., polyadenylation signals). Suchregulatory sequences are described, for example, in Goeddel, GeneExpression Technology: Methods in Enzymology 185, Academic Press, SanDiego, Calif. (1990). Regulatory sequences include those which directconstitutive expression of a nucleotide sequence in many types of hostcell and those which direct expression of the nucleotide sequence onlyin certain host cells (e.g., tissue-specific regulatory sequences). Itwill be appreciated by those skilled in the art that the design of theexpression vector can depend on such factors as the choice of the hostcell to be transformed, the level of expression of protein desired, etc.The expression vectors of the invention can be introduced into hostcells to thereby produce proteins or peptides, including fusion proteinsor peptides, encoded by nucleic acids as described herein.

[0640] The recombinant expression vectors of the invention can bedesigned for expression of a polypeptide of the invention in prokaryotic(e.g., E. coli) or eukaryotic cells (e.g., insect cells (usingbaculovirus expression vectors), yeast cells or mammalian cells).Suitable host cells are discussed further in Goeddel, supra.Alternatively, the recombinant expression vector can be transcribed andtranslated in vitro, for example using T7 promoter regulatory sequencesand T7 polymerase.

[0641] Expression of proteins in prokaryotes is most often carried outin E. coli with vectors containing constitutive or inducible promotersdirecting the expression of either fusion or non-fusion proteins. Fusionvectors add a number of amino acids to a protein encoded therein,usually to the amino terminus of the recombinant protein. Such fusionvectors typically serve three purposes: 1) to increase expression ofrecombinant protein; 2) to increase the solubility of the recombinantprotein; and 3) to aid in the purification of the recombinant protein byacting as a ligand in affinity purification. Often, in fusion expressionvectors, a proteolytic cleavage site is introduced at the junction ofthe fusion moiety and the recombinant protein to enable separation ofthe recombinant protein from the fusion moiety subsequent topurification of the fusion protein. Such enzymes, and their cognaterecognition sequences, include Factor Xa, thrombin and enterokinase.Typical fusion expression vectors include pGEX (Pharmacia Biotech Inc;Smith and Johnson (1988) Gene 67:31-40), pMAL (New England Biolabs,Beverly, Mass.) and pRIT5 (Pharmacia, Piscataway, N.J.) which fuseglutathione S-transferase (GST), maltose E binding protein, or proteinA, respectively, to the target recombinant protein.

[0642] Examples of suitable inducible non-fusion E. coli expressionvectors include pTrc (Amann et al., (1988) Gene 69:301-315) and pET 11d(Studier et al., Gene Expression Technology: Methods in Enzymology 185,Academic Press, San Diego, Calif. (1990) 60-89). Target gene expressionfrom the pTrc vector relies on host RNA polymerase transcription from ahybrid trp-lac fusion promoter. Target gene expression from the pET 11dvector relies on transcription from a T7 gn10-1ac fusion promotermediated by a coexpressed viral RNA polynerase (T7 gn1). This viralpolymerase is supplied by host strains BL21(DE3) or HMS174(DE3) from aresident λ prophage harboring a T7 gn1 gene under the transcriptionalcontrol of the lacUV 5 promoter.

[0643] One strategy to maximize recombinant protein expression in E.coli is to express the protein in a host bacteria with an impairedcapacity to proteolytically cleave the recombinant protein (Gottesman,Gene Expression Technology: Methods in Enzymology 185, Academic Press,San Diego, Calif. (1990) 119-128). Another strategy is to alter thenucleic acid sequence of the nucleic acid to be inserted into anexpression vector so that the individual codons for each amino acid arethose preferentially utilized in E. coli (Wada et al. (1992) NucleicAcids Res. 20:2111-2118). Such alteration of nucleic acid sequences ofthe invention can be carried out by standard DNA synthesis techniques.

[0644] In another embodiment, the expression vector is a yeastexpression vector. Examples of vectors for expression in yeast S.cerivisae include pYepSecl (Baldari et al. (1987) EMBO J. 6:229-234),pMFa (Kujan and Herskowitz, (1982) Cell 30:933-943), pJRY88 (Schultz etal. (1987) Gene 54:113-123), pYES2 (Invitrogen Corporation, San Diego,Calif.), and pPicZ (Invitrogen Corp, San Diego, Calif.).

[0645] Alternatively, the expression vector is a baculovirus expressionvector. Baculovirus vectors available for expression of proteins incultured insect cells (e.g., Sf9 cells) include the pAc series (Smith etal. (1983) Mol. Cell Biol. 3:2156-2165) and the pVL series (Lucklow andSummers (1989) Virology 170:31-39).

[0646] In yet another embodiment, a nucleic acid of the invention isexpressed in mammalian cells using a mammalian expression vector.Examples of mammalian expression vectors include pCDM8 (Seed (1987)Nature 329:840) and pMT2PC (Kaufmnan et al. (1987) EMBO J. 6:187-195).When used in mammalian cells, the expression vector's control functionsare often provided by viral regulatory elements. For example, commonlyused promoters are derived from polyoma, Adenovirus 2, cytomegalovirusand Simian Virus 40. For other suitable expression systems for bothprokaryotic and eukaryotic cells see chapters 16 and 17 of Sambrook etal., supra.

[0647] In another embodiment, the recombinant mammalian expressionvector is capable of directing expression of the nucleic acidpreferentially in a particular cell type (e.g., tissue-specificregulatory elements are used to express the nucleic acid).Tissue-specific regulatory elements are known in the art. Non-limitingexamples of suitable tissue-specific promoters include the albuminpromoter (liver-specific; Pinkert et al. (1987) Genes Dev. 1:268-277),lymphoid-specific promoters (Calame and Eaton (1988) Adv. Immunol.43:235-275), in particular promoters of T cell receptors (Winoto andBaltimore (1989) EMBO J. 8:729-733) and immunoglobulins (Baneiji et al.(1983) Cell 33:729-740; Queen and Baltimore (1983) Cell 33:741-748),neuron-specific promoters (e.g., the neurofilament promoter; Byrne andRuddle (1989) Proc. Natl. Acad. Sci. USA 86:5473-5477),pancreas-specific promoters (Edlund et al. (1985) Science 230:912-916),and mammary gland-specific promoters (e.g., milk whey promoter; U.S.Pat. No. 4,873,316 and European application Publication No. 264,166).Developmentally-regulated promoters are also encompassed, for examplethe murine hox promoters (Kessel and Gruss (1990) Science 249:374-379)and the a-fetoprotein promoter (Campes and Tilghman (1989) Genes Dev.3:537-546).

[0648] The invention further provides a recombinant expression vectorcomprising a DNA molecule of the invention cloned into the expressionvector in an antisense orientation. That is, the DNA molecule isoperably linked to a regulatory sequence in a manner which allows forexpression (by transcription of the DNA molecule) of an RNA moleculewhich is antisense to the MRNA encoding a polypeptide of the invention.Regulatory sequences operably linked to a nucleic acid cloned in theantisense orientation can be chosen which direct the continuousexpression of the antisense RNA molecule in a variety of cell types, forinstance viral promoters and/or enhancers, or regulatory sequences canbe chosen which direct constitutive, tissue specific or cell typespecific expression of antisense RNA. The antisense expression vectorcan be in the form of a recombinant plasmid, phagemid or attenuatedvirus in which antisense nucleic acids are produced under the control ofa high efficiency regulatory region, the activity of which can bedetermined by the cell type into which the vector is introduced. For adiscussion of the regulation of gene expression using antisense genessee Weintraub et al. (Reviews—Trends in Genetics, Vol. 1(1) 1986).

[0649] Another aspect of the invention pertains to host cells into whicha recombinant expression vector of the invention has been introduced.The terms “host cell” and “recombinant host cell” are usedinterchangeably herein. It is understood that such terms refer not onlyto the particular subject cell but to the progeny or potential progenyof such a cell. Because certain modifications may occur in succeedinggenerations due to either mutation or environmental influences, suchprogeny may not, in fact, be identical to the parent cell, but are stillincluded within the scope of the term as used herein.

[0650] A host cell can be any prokaryotic (e.g., E. coli) or eukaryoticcell (e.g., insect cells, yeast or mammalian cells).

[0651] Vector DNA can be introduced into prokaryotic or eukaryotic cellsvia conventional transformation or transfection techniques. As usedherein, the terms “transformation” and “transfection” are intended torefer to a variety of art-recognized techniques for introducing foreignnucleic acid into a host cell, including calcium phosphate or calciumchloride co-precipitation, DEAE-dextran-mediated transfection,lipofection, or electroporation. Suitable methods for transforming ortransfecting host cells can be found in Sambrook, et al. (supra), andother laboratory manuals.

[0652] For stable transfection of mammalian cells, it is known that,depending upon the expression vector and transfection technique used,only a small fraction of cells may integrate the foreign DNA into theirgenome. In order to identify and select these integrants, a gene thatencodes a selectable marker (e.g., for resistance to antibiotics) isgenerally introduced into the host cells along with the gene ofinterest. Preferred selectable markers include those which conferresistance to drugs, such as G418, hygromycin and methotrexate. Cellsstably transfected with the introduced nucleic acid can be identified bydrug selection (e.g., cells that have incorporated the selectable markergene will survive, while the other cells die).

[0653] In another embodiment, the expression characteristics of anendogenous (e.g., TANGO 239, TANGO 219, TANGO 232, TANGO 281, A236(INTERCEPT 236), TANGO 300, TANGO 353, TANGO 393, TANGO 402, TANGO 351and TANGO 509) gene within a cell, cell line or microorganism may bemodified by inserting a DNA regulatory element heterologous to theendogenous gene of interest into the genome of a cell, stable cell lineor cloned microorganism such that the inserted regulatory element isoperatively linked with the endogenous gene (e.g., TANGO 239, TANGO 219,TANGO 232, TANGO 281, A236 (INTERCEPT 236), TANGO 300, TANGO 353, TANGO393, TANGO 402, TANGO 351 and TANGO 509) and controls, modulates oractivates the endogenous gene. For example, endogenous genes of theinvention which are normally “transcriptionally silent”, i.e., geneswhich are normally not expressed, or are expressed only at very lowlevels in a cell line or microorganism, may be activated by inserting aregulatory element which is capable of promoting the expression of anormally expressed gene product in that cell line or microorganism.Alternatively, transcriptionally silent, endogenous genes of theinvention may be activated by insertion of a promiscuous regulatoryelement that works across cell types.

[0654] A heterologous regulatory element may be inserted into a stablecell line or cloned microorganism, such that it is operatively linkedwith and activates expression of endogenous TANGO 239, TANGO 219, TANGO232, TANGO 281, A236 (INTERCEPT 236), TANGO 300, TANGO 353, TANGO 393,TANGO 402, TANGO 351 and TANGO 509 genes, using techniques, such astargeted homologous recombination, which are well known to those ofskill in the art, and described e.g., in Chappel, U.S. Pat. No.5,272,071; PCT publication No. WO 91/06667, published May 16, 1991.

[0655] A host cell of the invention, such as a prokaryotic or eukaryotichost cell in culture, can be used to produce a polypeptide of theinvention. Accordingly, the invention further provides methods forproducing a polypeptide of the invention using the host cells of theinvention. In one embodiment, the method comprises culturing the hostcell of invention (into which a recombinant expression vector encoding apolypeptide of the invention has been introduced) in a suitable mediumsuch that the polypeptide is produced. In another embodiment, the methodfurther comprises isolating the polypeptide from the medium or the hostcell.

[0656] The host cells of the invention can also be used to producenonhuman transgenic animals. For example, in one embodiment, a host cellof the invention is a fertilized oocyte or an embryonic stem cell intowhich a sequence encoding a polypeptide of the invention has beenintroduced. Such host cells can then be used to create non-humantransgenic animals in which exogenous sequences encoding a polypeptideof the invention have been introduced into their genome or homologousrecombinant animals in which endogenous encoding a polypeptide of theinvention sequences have been altered. Such animals are useful forstudying the function and/or activity of the polypeptide and foridentifying and/or evaluating modulators of polypeptide activity. Inaddition to particular gene expression and/or polypeptide expressionphenotypes, the transgenic animals of the invention can exhibit any ofthe phenotypes (e.g., processes, disorder symptoms and/or disorders), asare described in the sections above. As used herein, a “transgenicanimal” is a non-human animal, preferably a mammal, more preferably arodent such as a rat or mouse, in which one or more of the cells of theanimal includes a transgene. Other examples of transgenic animalsinclude non-human primates, sheep, dogs, cows, goats, chickens,amphibians, etc. A transgene is exogenous DNA which is integrated intothe genome of a cell from which a transgenic animal develops and whichremains in the genome of the mature animal, thereby directing theexpression of an encoded gene product in one or more cell types ortissues of the transgenic animal. As used herein, an “homologousrecombinant animal” is a non-human animal, preferably a mammal, morepreferably a mouse, in which an endogenous gene has been altered byhomologous recombination between the endogenous gene and an exogenousDNA molecule introduced into a cell of the animal, e.g., an embryoniccell of the animal, prior to development of the animal.

[0657] A transgenic animal of the invention can be created byintroducing nucleic acid encoding a polypeptide of the invention (or ahomologue thereof) into the male pronuclei of a fertilized oocyte, e.g.,by microinjection, retroviral infection, and allowing the oocyte todevelop in a pseudopregnant female foster animal. Intronic sequences andpolyadenylation signals can also be included in the transgene toincrease the efficiency of expression of the transgene. Atissue-specific regulatory sequence(s) can be operably linked to thetransgene to direct expression of the polypeptide of the invention toparticular cells. Methods for generating transgenic animals via embryomanipulation and microinjection, particularly animals such as mice, havebecome conventional in the art and are described, for example, in U.S.Pat. Nos. 4,736,866 and 4,870,009, U.S. Pat. No. 4,873,191 and in Hogan,Manipulating the Mouse Embryo, (Cold Spring Harbor Laboratory Press,Cold Spring Harbor, N.Y., 1986) and Wakayama et al., (1999), Proc. Natl.Acad. Sci. USA, 96:14984-14989. Similar methods are used for productionof other transgenic animals. A transgenic founder animal can beidentified based upon the presence of the transgene in its genome and/orexpression of mRNA encoding the transgene in tissues or cells of theanimals. A transgenic founder animal can then be used to breedadditional animals carrying the transgene. Moreover, transgenic animalscarrying the transgene can further be bred to other transgenic animalscarrying other transgenes.

[0658] To create an homologous recombinant animal, a vector is preparedwhich contains at least a portion of a gene encoding a polypeptide ofthe invention into which a deletion, addition or substitution has beenintroduced to thereby alter, e.g., functionally disrupt, the gene. In apreferred embodiment, the vector is designed such that, upon homologousrecombination, the endogenous gene is functionally disrupted (i.e., nolonger encodes a functional protein; also referred to as a “knock out”vector). Alternatively, the vector can be designed such that, uponhomologous recombination, the endogenous gene is mutated or otherwisealtered but still encodes functional protein (e.g., the upstreamregulatory region can be altered to thereby alter the expression of theendogenous protein). In the homologous recombination vector, the alteredportion of the gene is flanked at its 5′ and 3′ends by additionalnucleic acid of the gene to allow for homologous recombination to occurbetween the exogenous gene carried by the vector and an endogenous genein an embryonic stem cell. The additional flanking nucleic acidsequences are of sufficient length for successful homologousrecombination with the endogenous gene. Typically, several kilobases offlanking DNA (both at the 5′ and 3′ ends) are included in the vector(see, e.g., Thomas and Capecchi (1987) Cell 51:503 for a description ofhomologous recombination vectors). The vector is introduced into anembryonic stem cell line (e.g., by electroporation) and cells in whichthe introduced gene has homologously recombined with the endogenous geneare selected (see, e.g., Li et al. (1992) Cell 69:915). The selectedcells are then injected into a blastocyst of an animal (e.g., a mouse)to form aggregation chimeras (see, e.g., Bradley in Teratocarcinomas andEmbryonic Stem Cells: A Practical Approach, Robertson, ed. (IRL, Oxford,1987) pp. 113-152). A chimeric embryo can then be implanted into asuitable pseudopregnant female foster animal and the embryo brought toterm. Progeny harboring the homologously recombined DNA in their germcells can be used to breed animals in which all cells of the animalcontain the homologously recombined DNA by germline transmission of thetransgene. Methods for constructing homologous recombination vectors andhomologous recombinant animals are described further in Bradley (1991)Current Opinion in Bio/Technology 2:823-829 and in PCT Publication Nos.WO 90/11354, WO 91/01140, WO 92/0968, and WO 93/04169.

[0659] In another embodiment, transgenic non-human animals can beproduced which contain selected systems which allow for regulatedexpression of the transgene. One example of such a system is thecre/loxP recombinase system of bacteriophage P1. For a description ofthe cre/loxP recombinase system, see, e.g., Lakso et al. (1992) Proc.Natl. Acad. Sci. USA 89:6232-6236. Another example of a recombinasesystem is the FLP recombinase system of Saccharomyces cerevisiae(O'Gorman et al. (1991) Science 251:1351-1355. If a cre/loxP recombinasesystem is used to regulate expression of the transgene, animalscontaining transgenes encoding both the Cre recombinase and a selectedprotein are required. Such animals can be provided through theconstruction of “double” transgenic animals, e.g., by mating twotransgenic animals, one containing a transgene encoding a selectedprotein and the other containing a transgene encoding a recombinase.

[0660] Clones of the non-human transgenic animals described herein canalso be produced according to the methods described in Wilmut et al.(1997) Nature 385:810-813 and PCT Publication NOS. WO 97/07668 and WO97/07669.

[0661] IV. Pharmaceutical Compositions

[0662] The nucleic acid molecules, polypeptides, and antibodies (alsoreferred to herein as “active compounds”) of the invention can beincorporated into pharmaceutical compositions suitable foradministration. Such compositions typically comprise the nucleic acidmolecule, protein, or antibody and a pharmaceutically acceptablecarrier. As used herein the language “pharmaceutically acceptablecarrier” is intended to include any and all solvents, dispersion media,coatings, antibacterial and antifungal agents, isotonic and absorptiondelaying agents, and the like, compatible with pharmaceuticaladministration. The use of such media and agents for pharmaceuticallyactive substances is well known in the art. Except insofar as anyconventional media or agent is incompatible with the active compound,use thereof in the compositions is contemplated. Supplementary activecompounds can also be incorporated into the compositions.

[0663] The invention includes methods for preparing pharmaceuticalcompositions for modulating the expression or activity of a polypeptideor nucleic acid of the invention. Such methods comprise formulating apharmaceutically acceptable carrier with an agent which modulatesexpression or activity of a polypeptide or nucleic acid of theinvention. Such compositions can further include additional activeagents. Thus, the invention further includes methods for preparing apharmaceutical composition by formulating a pharmaceutically acceptablecarrier with an agent which modulates expression or activity of apolypeptide or nucleic acid of the invention and one or more additionalactive compounds.

[0664] A pharmaceutical composition of the invention is formulated to becompatible with its intended route of administration. Examples of routesof administration include parenteral, e.g., intravenous, intradermal,subcutaneous, oral (e.g., inhalation), transdermal (topical),transmucosal, and rectal administration. Solutions or suspensions usedfor parenteral, intradermal, or subcutaneous application can include thefollowing components: a sterile diluent such as water for injection,saline solution, fixed oils, polyethylene glycols, glycerine, propyleneglycol or other synthetic solvents; antibacterial agents such as benzylalcohol or methyl parabens; antioxidants such as ascorbic acid or sodiumbisulfite; chelating agents such as ethylenediaminetetraacetic acid;buffers such as acetates, citrates or phosphates and agents for theadjustment of tonicity such as sodium chloride or dextrose. pH can beadjusted with acids or bases, such as hydrochloric acid or sodiumhydroxide. The parenteral preparation can be enclosed in ampoules,disposable syringes or multiple dose vials made of glass or plastic.

[0665] Pharmaceutical compositions suitable for injectable use includesterile aqueous solutions (where water soluble) or dispersions andsterile powders for the extemporaneous preparation of sterile injectablesolutions or dispersions. For intravenous administration, suitablecarriers include physiological saline, bacteriostatic water, CremophorEL™ (BASF; Parsippany, N.J.) or phosphate buffered saline (PBS). In allcases, the composition must be sterile and should be fluid to the extentthat easy syringability exists. It must be stable under the conditionsof manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (for example, glycerol, propylene glycol, andliquid polyetheylene glycol, and the like), and suitable mixturesthereof. The proper fluidity can be maintained, for example, by the useof a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersion and by the use of surfactants.Prevention of the action of microorganisms can be achieved by variousantibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In manycases, it will be preferable to include isotonic agents, for example,sugars, polyalcohols such as mannitol, sorbitol, sodium chloride in thecomposition. Prolonged absorption of the injectable compositions can bebrought about by including in the composition an agent which delaysabsorption, for example, aluminum monostearate and gelatin.

[0666] Sterile injectable solutions can be prepared by incorporating theactive compound (e.g., a polypeptide or antibody) in the required amountin an appropriate solvent with one or a combination of ingredientsenumerated above, as required, followed by filtered sterilization.Generally, dispersions are prepared by incorporating the active compoundinto a sterile vehicle which contains a basic dispersion medium and therequired other ingredients from those enumerated above. In the case ofsterile powders for the preparation of sterile injectable solutions, thepreferred methods of preparation are vacuum drying and freeze-dryingwhich yields a powder of the active ingredient plus any additionaldesired ingredient from a previously sterile-filtered solution thereof.

[0667] Oral compositions generally include an inert diluent or an ediblecarrier. They can be enclosed in gelatin capsules or compressed intotablets. For the purpose of oral therapeutic administration, the activecompound can be incorporated with excipients and used in the form oftablets, troches, or capsules. Oral compositions can also be preparedusing a fluid carrier for use as a mouthwash, wherein the compound inthe fluid carrier is applied orally and swished and expectorated orswallowed.

[0668] Pharmaceutically compatible binding agents, and/or adjuvantmaterials can be included as part of the composition. The tablets,pills, capsules, troches and the like can contain any of the followingingredients, or compounds of a similar nature: a binder such asmicrocrystalline cellulose, gum tragacanth or gelatin; an excipient suchas starch or lactose, a disintegrating agent such as alginic acid,Primogel, or corn starch; a lubricant such as magnesium stearate orSterotes; a glidant such as colloidal silicon dioxide; a sweeteningagent such as sucrose or saccharin; or a flavoring agent such aspeppermint, methyl salicylate, or orange flavoring.

[0669] For administration by inhalation, the compounds are delivered inthe form of an aerosol spray from a pressurized container or dispenserwhich contains a suitable propellant, e.g., a gas such as carbondioxide, or a nebulizer.

[0670] Systemic administration can also be by transmucosal ortransdermal means. For transmucosal or transdermal administration,penetrants appropriate to the barrier to be permeated are used in theformulation. Such penetrants are generally known in the art, andinclude, for example, for transmucosal administration, detergents, bilesalts, and fusidic acid derivatives. Transmucosal administration can beaccomplished through the use of nasal sprays or suppositories. Fortransdermal administration, the active compounds are formulated intoointments, salves, gels, or creams as generally known in the art.

[0671] The compounds can also be prepared in the form of suppositories(e.g., with conventional suppository bases such as cocoa butter andother glycerides) or retention enemas for rectal delivery.

[0672] In one embodiment, the active compounds are prepared withcarriers that will protect the compound against rapid elimination fromthe body, such as a controlled release formulation, including implantsand microencapsulated delivery systems. Biodegradable, biocompatiblepolymers can be used, such as ethylene vinyl acetate, polyanhydrides,polyglycolic acid, collagen, polyorthoesters, and polylactic acid.Methods for preparation of such formulations will be apparent to thoseskilled in the art. The materials can also be obtained commercially fromAlza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions(including liposomes targeted to infected cells with monoclonalantibodies to viral antigens) can also be used as pharmaceuticallyacceptable carriers. These can be prepared according to methods known tothose skilled in the art, for example, as described in U.S. Pat. No.4,522,811.

[0673] It is especially advantageous to formulate oral or parenteralcompositions in dosage unit form for ease of administration anduniformity of dosage. Dosage unit form as used herein refers tophysically discrete units suited as unitary dosages for the subject tobe treated; each unit containing a predetermined quantity of activecompound calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical carrier. The specificationfor the dosage unit forms of the invention are dictated by and directlydependent on the unique characteristics of the active compound and theparticular therapeutic effect to be achieved, and the limitationsinherent in the art of compounding such an active compound for thetreatment of individuals.

[0674] For antibodies, the preferred dosage is 0.1 mg/kg to 100 mg/kg ofbody weight (generally 10 mg/kg to 20 mg/kg). If the antibody is to actin the brain, a dosage of 50 mg/kg to 100 mg/kg is usually appropriate.Generally, partially human antibodies and fully human antibodies have alonger half-life within the human body than other antibodies.Accordingly, lower dosages and less frequent administration is oftenpossible. Modifications such as lipidation can be used to stabilizeantibodies and to enhance uptake and tissue penetration (e.g., into thebrain). A method for lipidation of antibodies is described by Cruikshanket al. ((1997) J. Acquired Immune Deficiency Syndromes and HumanRetrovirology 14:193).

[0675] Antibodies or antibodies conjugated to therapeutic moieties canbe administered to an individual alone or in combination with cytotoxicfactor(s), chemotherapeutic drug(s), and/or cytokine(s). If the latter,preferably, the antibodies are administered first and the cytotoxicfactor(s), chemotherapeutic drug(s) and/or cytokine(s) are administeredthereafter within 24 hours. The antibodies and cytotoxic factor(s),chemotherapeutic drug(s) and/or cytokine(s) can be administered bymultiple cycles depending upon the clinical response of the patient.Further, the antibodies and cytotoxic factor(s), chemotherapeuticdrug(s) and/or cytokine(s) can be administered by the same or separateroutes, for example, by intravenous, intranasal or intramuscularadministration. Cytotoxic factors include, but are not limited to,TNF-α, TNF-β, IL-1, IFN-γ and TIL-2. Chemotherapeutic drugs include, butare not limited to, 5-fluorouracil (5FU), vinblastine, actinomycin D,etoposide, cisplatin, methotrexate and doxorubicin. Cytokines include,but are not limited to, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9,IL-10 and IL-12.

[0676] As defined herein, a therapeutically effective amount of proteinor polypeptide (i.e., an effective dosage) ranges from about 0.001 to 30mg/kg body weight, preferably about 0.01 to 25 mg/kg body weight, morepreferably about 0.1 to 20 mg/kg body weight, and even more preferablyabout 1 to 10 mg/kg, 2 to 9 mg/kg, 3 to 8 mg/kg, 4 to 7 mg/kg, or 5 to 6mg/kg body weight.

[0677] The skilled artisan will appreciate that certain factors mayinfluence the dosage required to effectively treat a subject, includingbut not limited to the severity of the disease or disorder, previoustreatments, the general health and/or age of the subject, and otherdiseases present. Moreover, treatment of a subject with atherapeutically effective amount of a protein, polypeptide, or antibodycan include a single treatment or, preferably, can include a series oftreatments. In a preferred example, a subject is treated with antibody,protein, or polypeptide in the range of between about 0.1 to 20 mg/kgbody weight, one time per week for between about 1 to 10 weeks,preferably between 2 to 8 weeks, more preferably between about 3 to 7weeks, and even more preferably for about 4, 5, or 6 weeks. It will alsobe appreciated that the effective dosage of antibody, protein, orpolypeptide used for treatment may increase or decrease over the courseof a particular treatment. Changes in dosage may result and becomeapparent from the results of diagnostic assays as described herein.

[0678] The present invention encompasses agents which modulateexpression or activity. An agent may, for example, be a small molecule.For example, such small molecules include, but are not limited to,peptides, peptidomimetics, amino acids, amino acid analogs,polynucleotides, polynucleotide analogs, nucleotides, nucleotideanalogs, organic or inorganic compounds (i.e,. including heteroorganicand organometallic compounds) having a molecular weight less than about10,000 grams per mole, organic or inorganic compounds having a molecularweight less than about 5,000 grams per mole, organic or inorganiccompounds having a molecular weight less than about 1,000 grams permole, organic or inorganic compounds having a molecular weight less thanabout 500 grams per mole, and salts, esters, and other pharmaceuticallyacceptable forms of such compounds.

[0679] It is understood that appropriate doses of small molecule agentsdepends upon a number of factors within the ken of the ordinarilyskilled physician, veterinarian, or researcher. The dose(s) of the smallmolecule will vary, for example, depending upon the identity, size, andcondition of the subject or sample being treated, further depending uponthe route by which the composition is to be administered, if applicable,and the effect which the practitioner desires the small molecule to haveupon the nucleic acid or polypeptide of the invention. Exemplary dosesinclude milligram or microgram amounts of the small molecule perkilogram of subject or sample weight (e.g., about 1 microgram perkilogram to about 500 milligrams per kilogram, about 100 micrograms perkilogram to about 5 milligrams per kilogram, or about 1 microgram perkilogram to about 50 micrograms per kilogram. It is furthermoreunderstood that appropriate doses of a small molecule depend upon thepotency of the small molecule with respect to the expression or activityto be modulated. Such appropriate doses may be determined using theassays described herein. When one or more of these small molecules is tobe administered to an animal (e.g., a human) in order to modulateexpression or activity of a polypeptide or nucleic acid of theinvention, a physician, veterinarian, or researcher may, for example,prescribe a relatively low dose at first, subsequently increasing thedose until an appropriate response is obtained. In addition, it isunderstood that the specific dose level for any particular animalsubject will depend upon a variety of factors including the activity ofthe specific compound employed, the age, body weight, general health,gender, and diet of the subject, the time of administration, the routeof administration, the rate of excretion, any drug combination, and thedegree of expression or activity to be modulated.

[0680] The nucleic acid molecules of the invention can be inserted intovectors and used as gene therapy vectors. Gene therapy vectors can bedelivered to a subject by, for example, intravenous injection, localadministration (U.S. Pat. No. 5,328,470) or by stereotactic injection(see, e.g., Chen et al. (1994) Proc. Natl. Acad. Sci. USA 91:3054-3057).The pharmaceutical preparation of the gene therapy vector can includethe gene therapy vector in an acceptable diluent, or can comprise a slowrelease matrix in which the gene delivery vehicle is imbedded.Alternatively, where the complete gene delivery vector can be producedintact from recombinant cells, e.g., retroviral vectors, thepharmaceutical preparation can include one or more cells which producethe gene delivery system.

[0681] The pharmaceutical compositions can be included in a container,pack, or dispenser together with instructions for administration.

[0682] V. Uses and Methods of the Invention

[0683] The nucleic acid molecules, proteins, protein homologs, andantibodies described herein can be used in one or more of the followingmethods: a) screening assays; b) detection assays (e.g., chromosomalmapping, tissue typing, forensic biology); c) predictive medicine (e.g.,diagnostic assays, prognostic assays, monitoring clinical trials, andpharmacogenomics); and d) methods of treatment (e.g., therapeutic andprophylactic). For example, polypeptides of the invention can to used to(i) modulate cellular proliferation; (ii) modulate cellulardifferentiation; and/or (iii) modulate cellular adhesion. The isolatednucleic acid molecules of the invention can be used to express proteins(e.g., via a recombinant expression vector in a host cell in genetherapy applications), to detect mRNA (e.g., in a biological sample) ora genetic lesion, and to modulate activity of a polypeptide of theinvention. In addition, the polypeptides of the invention can be used toscreen drugs or compounds which modulate activity or expression of apolypeptide of the invention as well as to treat disorders characterizedby insufficient or excessive production of a protein of the invention orproduction of a form of a protein of the invention which has decreasedor aberrant activity compared to the wild type protein. In addition, theantibodies of the invention can be used to detect and isolate a proteinof the and modulate activity of a protein of the invention.

[0684] This invention further pertains to novel agents identified by theabove-described screening assays and uses thereof for treatments asdescribed herein.

[0685] A. Screening Assays

[0686] The invention provides a method (also referred to herein as a“screening assay”) for identifying modulators, i.e., candidate or testcompounds or agents (e.g., peptides, peptidomimetics, small molecules orother drugs) which bind to polypeptide of the invention or have astimulatory or inhibitory effect on, for example, expression or activityof a polypeptide of the invention.

[0687] In one embodiment, the invention provides assays for screeningcandidate or test compounds which bind to or modulate the activity ofthe membrane-bound form of a polypeptide of the invention orbiologically active portion thereof. The test compounds of the presentinvention can be obtained using any of the numerous approaches incombinatorial library methods known in the art, including: biologicallibraries; spatially addressable parallel solid phase or solution phaselibraries; synthetic library methods requiring deconvolution; the“one-bead one-compound” library method; and synthetic library methodsusing affinity chromatography selection. The biological library approachis limited to peptide libraries, while the other four approaches areapplicable to peptide, non-peptide oligomer or small molecule librariesof compounds (Lam (1997) Anticancer Drug Des. 12:145).

[0688] Examples of methods for the synthesis of molecular libraries canbe found in the art, for example in: DeWitt et al. (1993) Proc. Natl.Acad. Sci. USA 90:6909; Erb et al. (1994) Proc. Natl. Acad. Sci. USA91:11422; Zuckermann et al. (1994). J. Med. Chem. 37:2678; Cho et al.(1993) Science 261:1303; Carrell et al. (1994) Angew. Chem. Int. Ed.Engl. 33:2059; Carell et al. (1994) Angew. Chem. Int. Ed. Engl. 33:2061;and Gallop et al. (1994) J. Med. Chem. 37:1233.

[0689] Libraries of compounds may be presented in solution (e.g.,Houghten (1992) Bio/Techniques 13:412-421), or on beads (Lam (1991)Nature 354:82-84), chips (Fodor (1993) Nature 364:555-556), bacteria(U.S. Pat. No. 5,223,409), spores (U.S. Pat. Nos. 5,571,698; 5,403,484;and 5,223,409), plasmids (Cull et al. (1992) Proc. Natl. Acad. Sci. USA89:1865-1869) or phage (Scott and Smith (1990) Science 249:386-390;Devlin (1990) Science 249:404-406; Cwirla et al. (1990) Proc. Nati.Acad. Sci. USA 87:6378-6382; and Felici (1991) J. Mol. Biol.222:301-310).

[0690] In one embodiment, an assay is a cell-based assay in which a cellwhich expresses a membrane-bound form of a polypeptide of the invention,or a biologically active portion thereof, on the cell surface iscontacted with a test compound and the ability of the test compound tobind to the polypeptide determined. The cell, for example, can be ayeast cell or a cell of mammalian origin. Determining the ability of thetest compound to bind to the polypeptide can be accomplished, forexample, by coupling the test compound with a radioisotope or enzymaticlabel such that binding of the test compound to the polypeptide orbiologically active portion thereof can be determined by detecting thelabeled compound in a complex. For example, test compounds can belabeled with ¹²⁵I, ³⁵S, ¹⁴C, or ³H, either directly or indirectly, andthe radioisotope detected by direct counting of radioemmission or byscintillation counting. Alternatively, test compounds can beenzymatically labeled with, for example, horseradish peroxidase,alkaline phosphatase, or luciferase, and the enzymatic label detected bydetermination of conversion of an appropriate substrate to product. In apreferred embodiment, the assay comprises contacting a cell whichexpresses a membrane-bound form of a polypeptide of the invention, or abiologically active portion thereof, on the cell surface with a knowncompound which binds the polypeptide to form an assay mixture,contacting the assay mixture with a test compound, and determining theability of the test compound to interact with the polypeptide, whereindetermining the ability of the test compound to interact with thepolypeptide comprises determining the ability of the test compound topreferentially bind to the polypeptide or a biologically active portionthereof as compared to the known compound.

[0691] In another embodiment, an assay is a cell-based assay comprisingcontacting a cell expressing a membrane-bound form of a polypeptide ofthe invention, or a biologically active portion thereof, on the cellsurface with a test compound and determining the ability of the testcompound to modulate (e.g., stimulate or inhibit) the activity of thepolypeptide or biologically active portion thereof. Determining theability of the test compound to modulate the activity of the polypeptideor a biologically active portion thereof can be accomplished, forexample, by determining the ability of the polypeptide protein to bindto or interact with a target molecule.

[0692] Determining the ability of a polypeptide of the invention to bindto or interact with a target molecule can be accomplished by one of themethods described above for determining direct binding. As used herein,a “target molecule” is a molecule with which a selected polypeptide(e.g., a polypeptide of the invention) binds or interacts with innature, for example, a molecule on the surface of a cell which expressesthe selected protein, a molecule on the surface of a second cell, amolecule in the extracellular milieu, a molecule associated with theinternal surface of a cell membrane or a cytoplasmic molecule. A targetmolecule can be a polypeptide of the invention or some other polypeptideor protein. For example, a target molecule can be a component of asignal transduction pathway which facilitates transduction of anextracellular signal (e.g., a signal generated by binding of a compoundto a polypeptide of the invention) through the cell membrane and intothe cell or a second intercellular protein which has catalytic activityor a protein which facilitates the association of downstream signalingmolecules with a polypeptide of the invention. Determining the abilityof a polypeptide of the invention to bind to or interact with a targetmolecule can be accomplished by determining the activity of the targetmolecule. For example, the activity of the target molecule can bedetermined by detecting induction of a cellular second messenger of thetarget (e.g., intracellular Ca²⁺, diacylglycerol, IP3, etc.), detectingcatalytic/enzymatic activity of the target on an appropriate substrate,detecting the induction of a reporter gene (e.g., a regulatory elementthat is responsive to a polypeptide of the invention operably linked toa nucleic acid encoding a detectable marker, e.g., luciferase), ordetecting a cellular response, for example, cellular differentiation, orcell proliferation.

[0693] In yet another embodiment, an assay of the present invention is acell-free assay comprising contacting a polypeptide of the invention orbiologically active portion thereof with a test compound and determiningthe ability of the test compound to bind to the polypeptide orbiologically active portion thereof. Binding of the test compound to thepolypeptide can be determined either directly or indirectly as describedabove. In a preferred embodiment, the assay includes contacting thepolypeptide of the invention or biologically active portion thereof witha known compound which binds the polypeptide to form an assay mixture,contacting the assay mixture with a test compound, and determining theability of the test compound to interact with the polypeptide, whereindetermining the ability of the test compound to interact with thepolypeptide comprises determining the ability of the test compound topreferentially bind to the polypeptide or biologically active portionthereof as compared to the known compound.

[0694] In another embodiment, an assay is a cell-free assay comprisingcontacting a polypeptide of the invention or biologically active portionthereof with a test compound and determining the ability of the testcompound to modulate (e.g., stimulate or inhibit) the activity of thepolypeptide or biologically active portion thereof. Determining theability of the test compound to modulate the activity of the polypeptidecan be accomplished, for example, by determining the ability of thepolypeptide to bind to a target molecule by one of the methods describedabove for determining direct binding. In an alternative embodiment,determining the ability of the test compound to modulate the activity ofthe polypeptide can be accomplished by determining the ability of thepolypeptide of the invention to further modulate the target molecule.For example, the catalytic/enzymatic activity of the target molecule onan appropriate substrate can be determined as previously described.

[0695] In yet another embodiment, the cell-free assay comprisescontacting a polypeptide of the invention or biologically active portionthereof with a known compound which binds the polypeptide to form anassay mixture, contacting the assay mixture with a test compound, anddetermining the ability of the test compound to interact with thepolypeptide, wherein determining the ability of the test compound tointeract with the polypeptide comprises determining the ability of thepolypeptide to preferentially bind to or modulate the activity of atarget molecule.

[0696] The cell-free assays of the present invention are amenable to useof both a soluble form or the membrane-bound form of a polypeptide ofthe invention. In the case of cell-free assays comprising themembrane-bound form of the polypeptide, it may be desirable to utilize asolubilizing agent such that the membrane-bound form of the polypeptideis maintained in solution. Examples of such solubilizing agents includenon-ionic detergents such as n-octylglucoside, n-dodecylglucoside,n-octylmaltoside, octanoyl-N-methylglucamide,decanoyl-N-methylglucamide, Triton X-100, Triton X-1 14, Thesit,Isotridecypoly(ethylene glycol ether)n,3-[(3-cholamidopropyl)dimethylamminio]-1-propane sulfonate (CHAPS),3-[(3-cholamidopropyl)dimethylamminio]-2-hydroxy-1-propane sulfonate(CHAPSO), or N-dodecyl═N,N-dimethyl-3-ammonio-1-propane sulfonate.

[0697] In more than one embodiment of the above assay methods of thepresent invention, it may be desirable to immobilize either thepolypeptide of the invention or its target molecule to facilitateseparation of complexed from uncomplexed forms of one or both of theproteins, as well as to accommodate automation of the assay. Binding ofa test compound to the polypeptide, or interaction of the polypeptidewith a target molecule in the presence and absence of a candidatecompound, can be accomplished in any vessel suitable for containing thereactants. Examples of such vessels include microtitre plates, testtubes, and micro-centrifuge tubes. In one embodiment, a fusion proteincan be provided which adds a domain that allows one or both of theproteins to be bound to a matrix. For example, glutathione-S-transferasefusion proteins or glutathione-S-transferase fusion proteins can beadsorbed onto glutathione sepharose beads (Sigma Chemical; St. Louis,Mo.) or glutathione derivatized microtitre plates, which are thencombined with the test compound or the test compound and either thenon-adsorbed target protein or A polypeptide of the invention, and themixture incubated under conditions conducive to complex formation (e.g.,at physiological conditions for salt and pH). Following incubation, thebeads or microtitre plate wells are washed to remove any unboundcomponents and complex formation is measured either directly orindirectly, for example, as described above. Alternatively, thecomplexes can be dissociated from the matrix, and the level of bindingor activity of the polypeptide of the invention can be determined usingstandard techniques.

[0698] Other techniques for immobilizing proteins on matrices can alsobe used in the screening assays of the invention. For example, eitherthe polypeptide of the invention or its target molecule can beimmobilized utilizing conjugation of biotin and streptavidin.Biotinylated polypeptide of the invention or target molecules can beprepared from biotin-NHS (N-hydroxy-succinimide) using techniques wellknown in the art (e.g., biotinylation kit, Pierce Chemicals; Rockford,Ill.), and immobilized in the wells of streptavidin-coated 96 wellplates (Pierce Chemical). Alternatively, antibodies reactive with thepolypeptide of the invention or target molecules but which do notinterfere with binding of the polypeptide of the invention to its targetmolecule can be derivatized to the wells of the plate, and unboundtarget or polypeptide of the invention trapped in the wells by antibodyconjugation. Methods for detecting such complexes, in addition to thosedescribed above for the GST-immobilized complexes, includeimmunodetection of complexes using antibodies reactive with thepolypeptide of the invention or target molecule, as well asenzyme-linked assays which rely on detecting an enzymatic activityassociated with the polypeptide of the invention or target molecule.

[0699] In another embodiment, modulators of expression of a polypeptideof the invention are identified in a method in which a cell is contactedwith a candidate compound and the expression of the selected mRNA orprotein (i.e., the mRNA or protein corresponding to a polypeptide ornucleic acid of the invention) in the cell is determined. The level ofexpression of the selected mRNA or protein in the presence of thecandidate compound is compared to the level of expression of theselected MRNA or protein in the absence of the candidate compound. Thecandidate compound can then be identified as a modulator of expressionof the polypeptide of the invention based on this comparison. Forexample, when expression of the selected mRNA or protein is greater(statistically significantly greater) in the presence of the candidatecompound than in its absence, the candidate compound is identified as astimulator of the selected MRNA or protein expression. Alternatively,when expression of the selected mRNA or protein is less (statisticallysignificantly less) in the presence of the candidate compound than inits absence, the candidate compound is identified as an inhibitor of theselected mRNA or protein expression. The level of the selected mRNA orprotein expression in the cells can be determined by methods describedherein.

[0700] In yet another aspect of the invention, a polypeptide of theinventions can be used as “bait proteins” in a two-hybrid assay or threehybrid assay (see, e.g., U.S. Pat. No. 5,283,317; Zervos et al. (1993)Cell 72:223-232; Madura et al. (1993) J. Biol. Chem. 268:12046-12054;Bartel et al. (1993) Bio/Techniques 14:920-924; Iwabuchi et al. (1993)Oncogene 8:1693-1696; and PCT Publication No. WO 94/10300), to identifyother proteins, which bind to or interact with the polypeptide of theinvention and modulate activity of the polypeptide of the invention.Such binding proteins are also likely to be involved in the propagationof signals by the polypeptide of the inventions as, for example,upstream or downstream elements of a signaling pathway involving thepolypeptide of the invention.

[0701] This invention further pertains to novel agents identified by theabove-described screening assays and uses thereof for treatments asdescribed herein.

[0702] B. Detection Assays

[0703] Portions or fragments of the cDNA sequences identified herein(and the corresponding complete gene sequences) can be used in numerousways as polynucleotide reagents. For example, these sequences can beused to: (i) map their respective genes on a chromosome and, thus,locate gene regions associated with genetic disease; (ii) identify anindividual from a minute biological sample (tissue typing); and (iii)aid in forensic identification of a biological sample. Theseapplications are described in the subsections below.

[0704] 1. Chromosome Mapping

[0705] Once the sequence (or a portion of the sequence) of a gene hasbeen isolated, this sequence can be used to map the location of the geneon a chromosome. Accordingly, nucleic acid molecules described herein orfragments thereof, can be used to map the location of the correspondinggenes on a chromosome. The mapping of the sequences to chromosomes is animportant first step in correlating these sequences with genesassociated with disease.

[0706] Briefly, genes can be mapped to chromosomes by preparing PCRprimers (preferably 15-25 bp in length) from the sequence of a gene ofthe invention. Computer analysis of the sequence of a gene of theinvention can be used to rapidly select primers that do not span morethan one exon in the genomic DNA, thus complicating the amplificationprocess. These primers can then be used for PCR screening of somaticcell hybrids containing individual human chromosomes. Only those hybridscontaining the human gene corresponding to the gene sequences will yieldan amplified fragment. For a review of this technique, see D'Eustachioet al. ((1983) Science 220:919-924).

[0707] PCR mapping of somatic cell hybrids is a rapid procedure forassigning a particular sequence to a particular chromosome. Three ormore sequences can be assigned per day using a single thermal cycler.Using the nucleic acid sequences of the invention to designoligonucleotide primers, sublocalization can be achieved with panels offragments from specific chromosomes. Other mapping strategies which cansimilarly be used to map a gene to its chromosome include in situhybridization (described in Fan et al. (1990) Proc. Natl. Acad. Sci. USA87:6223-27), pre-screening with labeled flow-sorted chromosomes (CITE),and pre-selection by hybridization to chromosome specific cDNAlibraries. Fluorescence in situ hybridization (FISH) of a DNA sequenceto a metaphase chromosomal spread can further be used to provide aprecise chromosomal location in one step. For a review of thistechnique, see Verma et al., (Human Chromosomes: A Manual of BasicTechniques (Pergamon Press, New York, 1988)).

[0708] Reagents for chromosome mapping can be used individually to marka single chromosome or a single site on that chromosome, or panels ofreagents can be used for marking multiple sites and/or multiplechromosomes. Reagents corresponding to noncoding regions of the genesactually are preferred for mapping purposes. Coding sequences are morelikely to be conserved within gene families, thus increasing the chanceof cross hybridizations during chromosomal mapping.

[0709] Once a sequence has been mapped to a precise chromosomallocation, the physical position of the sequence on the chromosome can becorrelated with genetic map data. (Such data are found, for example, inV. McKusick, Mendelian Inheritance in Man, available on-line throughJohns Hopkins University Welch Medical Library). The relationshipbetween genes and disease, mapped to the same chromosomal region, canthen be identified through linkage analysis (co-inheritance ofphysically adjacent genes), described in, e.g., Egeland et al. (1987)Nature 325:783-787.

[0710] Moreover, differences in the DNA sequences between individualsaffected and unaffected with a disease associated with a gene of theinvention can be determined. If a mutation is observed in some or all ofthe affected individuals but not in any unaffected individuals, then themutation is likely to be the causative agent of the particular disease.Comparison of affected and unaffected individuals generally involvesfirst looking for structural alterations in the chromosomes such asdeletions or translocations that are visible from chromosome spreads ordetectable using PCR based on that DNA sequence. Ultimately, completesequencing of genes from several individuals can be performed to confirmthe presence of a mutation and to distinguish mutations frompolymorphisms.

[0711] Furthermore, the nucleic acid sequences disclosed herein can beused to perform searches against “mapping databases”, e.g., BLAST-typesearch, such that the chromosome position of the gene is identified bysequence homology or identity with known sequence fragments which havebeen mapped to chromosomes.

[0712] In the instant case, the human gene for TANGO 219 was mapped onradiation hybrid panels to the long arm of chromosome 5, in the regionq21-22. Flanking markers for this region are NIB916 and D5S492. TheMANA2 (mannosidase, type2), APC (adenomatous polyposis coli), PST(polysialytransferase), CAST (calpastatin) genes also map to this regionof the human chromosome. The LGMD1A (limb girdle muscular dystrophy)loci also maps to this region of the human chromosome. This region issyntenic to mouse chromosomes 11 and 18. The Q (quinky), pdwproportional dwarf), and lyl1 (lymphoblastomic leukemia) loci also mapto this region of the mouse chromosome. The Chr. 11-fer (protein kinase,testis specific) Chr. 18-mcc (mutated in colorectal cancers), pk(plucked), don1 (divergent of neuregulin 1) genes also map to thisregion of the mouse chromosome.

[0713] In the instant case, the human gene for TANGO 232 was mapped onradiation hybrid panels to the long arm of chromosome 11, in the regionql3. Flanking markers for this region are D11S1965 and WI-1 409. TheARRB1 (arrestin, beta), GIF (gastric intrinsic factor), ACTN3 (actinin,alpha 3) genes also map to this region of the human chromosome. The HBM(high bone mass), OPTB1 (osteoporosis, auto.rec.), OPPG (osteoporosis,pseudoglioma syndrome), BBS1 (Bardet-Bied1 syndrome), HND (Hartnupdisorder), MKS2 (Meckel syndrome 2) This region is syntenic to mousechromosome 7. The oc (osteosclerotic), dc (dancer), nmd (meuromusculardegeneration), ocd (osteochondrodystrophy) loci also map to this regionof the mouse chromosome. The pcx (pyruvate decarboxylase), chk (cholinekinase), gain (galanin) genes also map to this region of the mousechromosome.

[0714] In the instant case, human TANGO 393 maps by homology to ESTs toChromosome 22 between D22S420 and D22S446.

[0715] In addition, a polypeptide and fragments and sequences thereofand antibodies specific thereto can be used to map the location of thegene encoding the polypeptide on a chromosome. This mapping can becarried out by specifically detecting the presence of the polypeptide inmembers of a panel of somatic cell hybrids between cells of a firstspecies of animal from which the protein originates and cells from asecond species of animal and then determining which somatic cellhybrid(s) expresses the polypeptide and noting the chromosome(s) fromthe first species of animal that it contains. For examples of thistechnique, see Pajunen et al. (1988) Cytogenet. Cell Genet. 47:37-41 andVan Keuren et al. (1986) Hum. Genet. 74:34-40. Alternatively, thepresence of the polypeptide in the somatic cell hybrids can bedetermined by assaying an activity or property of the polypeptide, forexample, enzymatic activity, as described in Bordelon-Riser et al.(1979) Somatic Cell Genetics 5:597-613 and Owerbach et al. (1978) Proc.Natl. Acad. Sci. USA 75:5640-5644.

[0716] 2. Tissue Typing

[0717] The nucleic acid sequences of the present invention can also beused to identify individuals from minute biological samples. The UnitedStates military, for example, is considering the use of restrictionfragment length polymorphism (RFLP) for identification of its personnel.In this technique, an individual's genomic DNA is digested with one ormore restriction enzymes, and probed on a Southern blot to yield uniquebands for identification. This method does not suffer from the currentlimitations of “Dog Tags” which can be lost, switched, or stolen, makingpositive identification difficult. The sequences of the presentinvention are useful as additional DNA markers for RFLP (described inU.S. Pat. No. 5,272,057).

[0718] Furthermore, the sequences of the present invention can be usedto provide an alternative technique which determines the actualbase-by-base DNA sequence of selected portions of an individual'sgenome. Thus, the nucleic acid sequences described herein can be used toprepare two PCR primers from the 5′ and 3′ ends of the sequences. Theseprimers can then be used to amplify an individual's DNA and subsequentlysequence it.

[0719] Panels of corresponding DNA sequences from individuals, preparedin this manner, can provide unique individual identifications, as eachindividual will have a unique set of such DNA sequences due to allelicdifferences. The sequences of the present invention can be used toobtain such identification sequences from individuals and from tissue.The nucleic acid sequences of the invention uniquely represent portionsof the human genome. Allelic variation occurs to some degree in thecoding regions of these sequences, and to a greater degree in thenoncoding regions. It is estimated that allelic variation betweenindividual humans occurs with a frequency at about once per each 500bases. Each of the sequences described herein can, to some degree, beused as a standard against which DNA from an individual can be comparedfor identification purposes. Because greater numbers of polymorphismsoccur in the noncoding regions, fewer sequences are necessary todifferentiate individuals. The noncoding sequences of SEQ ID NO: 1, 3,5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41,or 43 can comfortably provide positive individual identification with apanel of perhaps 10 to 1,000 primers which each yield a noncodingamplified sequence of 100 bases. If predicted coding sequences of any ofSEQ ID NO: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31,33, 35, 37, 39, 41, or 43 are used, a more appropriate number of primersfor positive individual identification would be 500-2,000.

[0720] If a panel of reagents from the nucleic acid sequences describedherein is used to generate a unique identification database for anindividual, those same reagents can later be used to identify tissuefrom that individual. Using the unique identification database, positiveidentification of the individual, living or dead, can be made fromextremely small tissue samples.

[0721] 3. Use of Partial Gene Sequences in Forensic Biology

[0722] DNA-based identification techniques can also be used in forensicbiology. Forensic biology is a scientific field employing genetic typingof biological evidence found at a crime scene as a means for positivelyidentifying, for example, a perpetrator of a crime. To make such anidentification, PCR technology can be used to amplify DNA sequencestaken from very small biological samples such as tissues, e.g., hair orskin, or body fluids, e.g., blood, saliva, or semen found at a crimescene. The amplified sequence can then be compared to a standard,thereby allowing identification of the origin of the biological sample.

[0723] The sequences of the present invention can be used to providepolynucleotide reagents, e.g., PCR primers, targeted to specific loci inthe human genome, which can enhance the reliability of DNA-basedforensic identifications by, for example, providing another“identification marker” (i.e. another DNA sequence that is unique to aparticular individual). As mentioned above, actual base sequenceinformation can be used for identification as an accurate alternative topatterns formed by restriction enzyme generated fragments. Sequencestargeted to noncoding regions are particularly appropriate for this useas greater numbers of polymorphisms occur in the noncoding regions,making it easier to differentiate individuals using this technique.Examples of polynucleotide reagents include the nucleic acid sequencesof the invention or portions thereof, e.g., fragments derived fromnoncoding regions having a length of at least 20 or 30 bases.

[0724] The nucleic acid sequences described herein can further be usedto provide polynucleotide reagents, e.g., labeled or labelable probeswhich can be used in, for example, an in situ hybridization technique,to identify a specific tissue, e.g., brain tissue. This can be veryuseful in cases where a forensic pathologist is presented with a tissueof unknown origin. Panels of such probes can be used to identify tissueby species and/or by organ type.

[0725] C. Predictive Medicine

[0726] The present invention also pertains to the field of predictivemedicine in which diagnostic assays, prognostic assays,pharmacogenomics, and monitoring clinical trails are used for prognostic(predictive) purposes to thereby treat an individual prophylactically.Accordingly, one aspect of the present invention relates to diagnosticassays for determining expression of a polypeptide or nucleic acid ofthe invention and/or activity of a polypeptide of the invention, in thecontext of a biological sample (e.g., blood, serum, cells, tissue) tothereby determine whether an individual is afflicted with a disease ordisorder, or is at risk of developing a disorder, associated withaberrant expression or activity of a polypeptide of the invention, suchas a proliferative disorder, e.g., psoriasis or cancer, or an angiogenicdisorder. The invention also provides for prognostic (or predictive)assays for determining whether an individual is at risk of developing adisorder associated with aberrant expression or activity of apolypeptide of the invention. For example, mutations in a gene of theinvention can be assayed in a biological sample. Such assays can be usedfor prognostic or predictive purpose to thereby prophylactically treatan individual prior to the onset of a disorder characterized by orassociated with aberrant expression or activity of a polypeptide of theinvention.

[0727] Another aspect of the invention provides methods for expressionof a nucleic acid or polypeptide of the invention or activity of apolypeptide of the invention in an individual to thereby selectappropriate therapeutic or prophylactic agents for that individual(referred to herein as “pharmacogenomics”). Pharmacogenomics allows forthe selection of agents (e.g., drugs) for therapeutic or prophylactictreatment of an individual based on the genotype of the individual(e.g., the genotype of the individual examined to determine the abilityof the individual to respond to a particular agent).

[0728] Yet another aspect of the invention pertains to monitoring theinfluence of agents (e.g., drugs or other compounds) on the expressionor activity of a polypeptide of the invention in clinical trials. Theseand other agents are described in further detail in the followingsections.

[0729] 1. Diagnostic Assays

[0730] An exemplary method for detecting the presence or absence of apolypeptide or nucleic acid of the invention in a biological sampleinvolves obtaining a biological sample from a test subject andcontacting the biological sample with a compound or an agent capable ofdetecting a polypeptide or nucleic acid (e.g., MRNA, genomic DNA) of theinvention such that the presence of a polypeptide or nucleic acid of theinvention is detected in the biological sample. A preferred agent fordetecting mRNA or genomic DNA encoding a polypeptide of the invention isa labeled nucleic acid probe capable of hybridizing to mRNA or genomicDNA encoding a polypeptide of the invention. The nucleic acid probe canbe, for example, a full-length CDNA, such as the nucleic acid of SEQ IDNO: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35,37, 39, 41, or 43 or a portion thereof, such as an oligonucleotide of atleast 15, 30, 50, 100, 250 or 500 contiguous nucleotides in length andsufficient to specifically hybridize under stringent conditions to amRNA or genomic DNA encoding a polypeptide of the invention. Othersuitable probes for use in the diagnostic assays of the invention aredescribed herein.

[0731] A preferred agent for detecting a polypeptide of the invention isan antibody capable of binding to a polypeptide of the invention,preferably an antibody with a detectable label. Antibodies can bepolyclonal, or more preferably, monoclonal. An intact antibody, or afragment thereof (e.g., Fab or F(ab′)₂) can be used. The term “labeled”,with regard to the probe or antibody, is intended to encompass directlabeling of the probe or antibody by coupling (i.e., physically linking)a detectable substance to the probe or antibody, as well as indirectlabeling of the probe or antibody by reactivity with another reagentthat is directly labeled. Examples of indirect labeling includedetection of a primary antibody using a fluorescently labeled secondaryantibody and end-labeling of a DNA probe with biotin such that it can bedetected with fluorescently labeled streptavidin. The term “biologicalsample” is intended to include tissues, cells and biological fluidsisolated from a subject, as well as tissues, cells and fluids presentwithin a subject. That is, the detection method of the invention can beused to detect mRNA, protein, or genomic DNA in a biological sample invitro as well as in vivo. For example, in vitro techniques for detectionof mRNA include Northern hybridizations and in situ hybridizations. Invitro techniques for detection of a polypeptide of the invention includeenzyme linked immunosorbent assays (ELISAs), Western blots,immunoprecipitations and immunofluorescence. In vitro techniques fordetection of genomic DNA include Southern hybridizations. Furthermore,in vivo techniques for detection of a polypeptide of the inventioninclude introducing into a subject a labeled antibody directed againstthe polypeptide. For example, the antibody can be labeled with aradioactive marker whose presence and location in a subject can bedetected by standard imaging techniques.

[0732] In one embodiment, the biological sample contains proteinmolecules from the test subject. Alternatively, the biological samplecan contain mRNA molecules from the test subject or genomic DNAmolecules from the test subject. A preferred biological sample is aperipheral blood leukocyte sample isolated by conventional means from asubject.

[0733] In another embodiment, the methods further involve obtaining acontrol biological sample from a control subject, contacting the controlsample with a compound or agent capable of detecting a polypeptide ofthe invention or mRNA or genomic DNA encoding a polypeptide of theinvention, such that the presence of the polypeptide or mRNA or genomicDNA encoding the polypeptide is detected in the biological sample, andcomparing the presence of the polypeptide or MRNA or genomic DNAencoding the polypeptide in the control sample with the presence of thepolypeptide or MRNA or genomic DNA encoding the polypeptide in the testsample.

[0734] The invention also encompasses kits for detecting the presence ofa polypeptide or nucleic acid of the invention in a biological sample (atest sample). Such kits can be used to determine if a subject issuffering from or is at increased risk of developing a disorderassociated with aberrant expression of a polypeptide of the invention asdiscussed, for example, in sections above relating to uses of thesequences of the invention.

[0735] For example, kits can be used to determine if a subject issuffering from or is at increased risk of disorders such asimmunological disorders, e.g., autoimmune disorders (e.g., arthritis,graft rejection (e.g., allograft rejection), T cell disorders (e.g.,AIDS) and inflammatory disorders (e.g., bacterial infection, psoriasis,septicemia, cerebral malaria, inflammatory bowel disease, arthritis(e.g., rheumatoid arthritis, osteoarthritis), and allergic inflammatorydisorders (e.g., asthma, psoriasis), neurological disorders, eyedisorders and embryonic disorders, which are associated with aberrantexpression of a polypeptide of the invention.

[0736] In another example, kits can be used to determine if a subject issuffering from or is at risk for brain-related disorders, inflammations,and tumors, and to treat injury or trauma to the brain, which areassociated with aberrant activity and/or expression of a polypeptide ofthe invention.

[0737] In another example, kits can be used to determine if a subject issuffering from or is at risk for ion transport disorders which areassociated with aberrant expression of a polypeptide of the invention.In another example, kits can be used to determine if a subject issuffering from or is at risk a disorder which is associated withaberrant expression of a polypeptide of the invention. In anotherexample, kits can be used to determine if a subject is suffering from oris at risk for a disorder associated with aberrant expression of apolypeptide of the invention.

[0738] The kit, for example, can comprise a labeled compound or agentcapable of detecting the polypeptide or MRNA encoding the polypeptide ina biological sample and means for determining the amount of thepolypeptide or mRNA in the sample (e.g., an antibody which binds thepolypeptide or an oligonucleotide probe which binds to DNA or mRNAencoding the polypeptide). Kits can also include instructions forobserving that the tested subject is suffering from or is at risk ofdeveloping a disorder associated with aberrant expression of thepolypeptide if the amount of the polypeptide or MRNA encoding thepolypeptide is above or below a normal level.

[0739] For antibody-based kits, the kit can comprise, for example: (1) afirst antibody (e.g., attached to a solid support) which binds to apolypeptide of the invention; and, optionally, (2) a second, differentantibody which binds to either the polypeptide or the first antibody andis conjugated to a detectable agent.

[0740] For oligonucleotide-based kits, the kit can comprise, forexample: (1) an oligonucleotide, e.g., a detectably labeledoligonucleotide, which hybridizes to a nucleic acid sequence encoding apolypeptide of the invention or (2) a pair of primers useful foramplifying a nucleic acid molecule encoding a polypeptide of theinvention. The kit can also comprise, e.g., a buffering agent, apreservative, or a protein stabilizing agent. The kit can also comprisecomponents necessary for detecting the detectable agent (e.g., an enzymeor a substrate). The kit can also contain a control sample or a seriesof control samples which can be assayed and compared to the test samplecontained. Each component of the kit is usually enclosed within anindividual container and all of the various containers are within asingle package along with instructions for observing whether the testedsubject is suffering from or is at risk of developing a disorderassociated with aberrant expression of the polypeptide.

[0741] 2. Prognostic Assays

[0742] The methods described herein can furthermore be utilized asdiagnostic or prognostic assays to identify subjects having or at riskof developing a disease or disorder associated with aberrant expressionor activity of a polypeptide of the invention. For example, the assaysdescribed herein, such as the preceding diagnostic assays or thefollowing assays, can be utilized to identify a subject having or atrisk of developing a disorder associated with aberrant expression oractivity of a polypeptide of the invention, e.g., an immunologicdisorder, or embryonic disorders. Alternatively, the prognostic assayscan be utilized to identify a subject having or at risk for developingsuch a disease or disorder. Thus, the present invention provides amethod in which a test sample is obtained from a subject and apolypeptide or nucleic acid (e.g., mRNA, genomic DNA) of the inventionis detected, wherein the presence of the polypeptide or nucleic acid isdiagnostic for a subject having or at risk of developing a disease ordisorder associated with aberrant expression or activity of thepolypeptide. As used herein, a “test sample” refers to a biologicalsample obtained from a subject of interest. For example, a test samplecan be a biological fluid (e.g., serum), cell sample, or tissue.

[0743] The prognostic assays described herein, for example, can be usedto identify a subject having or at risk of developing disorders such asdisorders discussed, for example, in sections above relating to uses ofthe sequences of the invention.

[0744] In another example, prognostic assays described herein can beused to identify a subject having or at risk of developing relateddisorders associated with expression of polypeptides of the invention.

[0745] Furthermore, the prognostic assays described herein can be usedto determine whether a subject can be administered an agent (e.g., anagonist, antagonist, peptidomimetic, protein, peptide, nucleic acid,small molecule, or other drug candidate) to treat a disease or disorderassociated with aberrant expression or activity of a polypeptide of theinvention. For example, such methods can be used to determine whether asubject can be effectively treated with a specific agent or class ofagents (e.g., agents of a type which decrease activity of thepolypeptide). Thus, the present invention provides methods fordetermining whether a subject can be effectively treated with an agentfor a disorder associated with aberrant expression or activity of apolypeptide of the invention in which a test sample is obtained and thepolypeptide or nucleic acid encoding the polypeptide is detected (e.g.,wherein the presence of the polypeptide or nucleic acid is diagnosticfor a subject that can be administered the agent to treat a disorderassociated with aberrant expression or activity of the polypeptide).

[0746] The methods of the invention can also be used to detect geneticlesions or mutations in a gene of the invention, thereby determining ifa subject with the lesioned gene is at risk for a disorder characterizedaberrant expression or activity of a polypeptide of the invention. Inpreferred embodiments, the methods include detecting, in a sample ofcells from the subject, the presence or absence of a genetic lesion ormutation characterized by at least one of an alteration affecting theintegrity of a gene encoding the polypeptide of the invention, or themis-expression of the gene encoding the polypeptide of the invention.For example, such genetic lesions or mutations can be detected byascertaining the existence of at least one of: 1) a deletion of one ormore nucleotides from the gene; 2) an addition of one or morenucleotides to the gene; 3) a substitution of one or more nucleotides ofthe gene; 4) a chromosomal rearrangement of the gene; 5) an alterationin the level of a messenger RNA transcript of the gene; 6) an aberrantmodification of the gene, such as of the methylation pattern of thegenomic DNA; 7) the presence of a non-wild type splicing pattern of amessenger RNA transcript of the gene; 8) a non-wild type level of a theprotein encoded by the gene; 9) an allelic loss of the gene; and 10) aninappropriate post-translational modification of the protein encoded bythe gene. As described herein, there are a large number of assaytechniques known in the art which can be used for detecting lesions in agene.

[0747] In certain embodiments, detection of the lesion involves the useof a probe/primer in a polymerase chain reaction (PCR) (see, e.g., U.S.Pat. Nos. 4,683,195 and 4,683,202), such as anchor PCR or RACE PCR, or,alternatively, in a ligation chain reaction (LCR) (see, e.g., Landegranet al. (1988) Science 241:1077-1080; and Nakazawa et al. (1994) Proc.Natl. Acad. Sci. USA 91:360-364), the latter of which can beparticularly useful for detecting point mutations in a gene (see, e.g.,Abravaya et al. (1995) Nucleic Acids Res. 23:675-682). This method caninclude the steps of collecting a sample of cells from a patient,isolating nucleic acid (e.g., genomic, niRNA or both) from the cells ofthe sample, contacting the nucleic acid sample with one or more primerswhich specifically hybridize to the selected gene under conditions suchthat hybridization and amplification of the gene (if present) occurs,and detecting the presence or absence of an amplification product, ordetecting the size of the amplification product and comparing the lengthto a control sample. It is anticipated that PCR and/or LCR may bedesirable to use as a preliminary amplification step in conjunction withany of the techniques used for detecting mutations described herein.

[0748] Alternative amplification methods include: self sustainedsequence replication (Guatelli et al. (1990) Proc. Natl. Acad. Sci. USA87:1874-1878), transcriptional amplification system (Kwoh, et al. (1989)Proc. Natl. Acad. Sci. USA 86:1173-1177), Q-Beta Replicase (Lizardi etal. (1988) Bio/Technology 6:1197), or any other nucleic acidamplification method, followed by the detection of the amplifiedmolecules using techniques well known to those of skill in the art.These detection schemes are especially useful for the detection ofnucleic acid molecules if such molecules are present in very lownumbers.

[0749] In an alternative embodiment, mutations in a selected gene from asample cell can be identified by alterations in restriction enzymecleavage patterns. For example, sample and control DNA is isolated,amplified (optionally), digested with one or more restrictionendonucleases, and fragment length sizes are determined by gelelectrophoresis and compared. Differences in fragment length sizesbetween sample and control DNA indicates mutations in the sample DNA.Moreover, the use of sequence specific ribozymes (see, e.g., U.S. Pat.No. 5,498,531) can be used to score for the presence of specificmutations by development or loss of a ribozyme cleavage site.

[0750] In other embodiments, genetic mutations can be identified byhybridizing a sample and control nucleic acids, e.g., DNA or RNA, tohigh density arrays containing hundreds or thousands of oligonucleotidesprobes (Cronin et al. (1996) Human Mutation 7:244-255; Kozal et al.(1996) Nature Medicine 2:753-759). For example, genetic mutations can beidentified in two-dimensional arrays containing light-generated DNAprobes as described in Cronin et al., supra. Briefly, a firsthybridization array of probes can be used to scan through long stretchesof DNA in a sample and control to identify base changes between thesequences by making linear arrays of sequential overlapping probes. Thisstep allows the identification of point mutations. This step is followedby a second hybridization array hat allows the characterization ofspecific mutations by using smaller, specialized probe arrayscomplementary to all variants or mutations detected. Each mutation arrayis composed of parallel probe sets, one complementary to the wild-typegene and the other complementary to the mutant gene.

[0751] In yet another embodiment, any of a variety of sequencingreactions known in the art can be used to directly sequence the selectedgene and detect mutations by comparing the sequence of the samplenucleic acids with the corresponding wild-type (control) sequence.Examples of sequencing reactions include those based on techniquesdeveloped by Maxim and Gilbert ((1977) Proc. Natl. Acad. Sci. USA74:560) or Sanger ((1977) Proc. Natl. Acad. Sci. USA 74:5463). It isalso contemplated that any of a variety of automated sequencingprocedures can be utilized when performing the diagnostic assays ((1995)Bio/Techniques 19:448), including sequencing by mass spectrometry (see,e.g., PCT Publication No. WO 94/16101; Cohen et al. (1996) Adv.Chromatogr. 36:127-162; and Griffin et al. (1993) Appl. Biochem.Biotechnol. 38:147-159).

[0752] Other methods for detecting mutations in a selected gene includemethods in which protection from cleavage agents is used to detectmismatched bases in RNA/RNA or RNA/DNA heteroduplexes (Myers et al.(1985) Science 230:1242). In general, the technique of “mismatchcleavage” entails providing heteroduplexes formed by hybridizing(labeled) RNA or DNA containing the wild-type sequence with potentiallymutant RNA or DNA obtained from a tissue sample. The double-strandedduplexes are treated with an agent which cleaves single-stranded regionsof the duplex such as which will exist due to basepair mismatchesbetween the control and sample strands. RNA/DNA duplexes can be treatedwith RNase to digest mismatched regions, and DNA/DNA hybrids can betreated with S1 nuclease to digest mismatched regions.

[0753] In other embodiments, either DNA/DNA or RNA/DNA duplexes can betreated with hydroxylamine or osmium tetroxide and with piperidine inorder to digest mismatched regions. After digestion of the mismatchedregions, the resulting material is then separated by size on denaturingpolyacrylamide gels to determine the site of mutation. See, e.g., Cottonet al. (1988) Proc. Natl. Acad. Sci. USA 85:4397; Saleeba et al. (1992)Methods Enzymol. 217:286-295. In a preferred embodiment, the control DNAor RNA can be labeled for detection.

[0754] In still another embodiment, the mismatch cleavage reactionemploys one or more proteins that recognize mismatched base pairs indouble-stranded DNA (so called “DNA mismatch repair” enzymes) in definedsystems for detecting and mapping point mutations in cDNAs obtained fromsamples of cells. For example, the mutY enzyme of E. coli cleaves A atG/A mismatches and the thymidine DNA glycosylase from HeLa cells cleavesT at G/T mismatches (Hsu et al. (1994) Carcinogenesis 15:1657-1662).According to an exemplary embodiment, a probe based on a selectedsequence, e.g., a wild-type sequence, is hybridized to a cDNA or otherDNA product from a test cell(s). The duplex is treated with a DNAmismatch repair enzyme, and the cleavage products, if any, can bedetected from electrophoresis protocols or the like. See, e.g., U.S.Pat. No. 5,459,039.

[0755] In other embodiments, alterations in electrophoretic mobilitywill be used to identify mutations in genes. For example, single strandconformation polymorphism (SSCP) may be used to detect differences inelectrophoretic mobility between mutant and wild type nucleic acids(Orita et al. (1989) Proc. Natl. Acad. Sci. USA 86:2766; see also Cotton(1993) Mutat. Res. 285:125-144; Hayashi (1992) Genet. Anal. Tech. Appl.9:73-79). Single-stranded DNA fragments of sample and control nucleicacids will be denatured and allowed to renature. The secondary structureof single-stranded nucleic acids varies according to sequence, and theresulting alteration in electrophoretic mobility enables the detectionof even a single base change. The DNA fragments may be labeled ordetected with labeled probes. The sensitivity of the assay may beenhanced by using RNA (rather than DNA), in which the secondarystructure is more sensitive to a change in sequence. In a preferredembodiment, the subject method utilizes heteroduplex analysis toseparate double stranded heteroduplex molecules on the basis of changesin electrophoretic mobility (Keen et al. (1991) Trends Genet. 7:5).

[0756] In yet another embodiment, the movement of mutant or wild-typefragments in polyacrylamide gels containing a gradient of denaturant isassayed using denaturing gradient gel electrophoresis (DGGE) (Myers etal. (1985) Nature 313:495). When DGGE is used as the method of analysis,DNA will be modified to insure that it does not completely denature, forexample by adding a 'GC clamp of approximately 40 bp of high-meltingGC-rich DNA by PCR. In a further embodiment, a temperature gradient isused in place of a denaturing gradient to identify differences in themobility of control and sample DNA (Rosenbaum and Reissner (1987)Biophys. Chem. 265:12753).

[0757] Examples of other techniques for detecting point mutationsinclude, but are not limited to, selective oligonucleotidehybridization, selective amplification, or selective primer extension.For example, oligonucleotide primers may be prepared in which the knownmutation is placed centrally and then hybridized to target DNA underconditions which permit hybridization only if a perfect match is found(Saiki et al. (1986) Nature 324:163); Saiki et al. (1989) Proc. Natl.Acad. Sci. USA 86:6230). Such allele specific oligonucleotides arehybridized to PCR amplified target DNA or a number of differentmutations when the oligonucleotides are attached to the hybridizingmembrane and hybridized with labeled target DNA.

[0758] Alternatively, allele specific amplification technology whichdepends on selective PCR amplification may be used in conjunction withthe instant invention. Oligonucleotides used as primers for specificamplification may carry the mutation of interest in the center of themolecule (so that amplification depends on differential hybridization)(Gibbs et al. (1989) Nucleic Acids Res. 17:2437-2448) or at the extreme3′ end of one primer where, under appropriate conditions, mismatch canprevent or reduce polymerase extension (Prossner (1993) Tibtech 11:238).In addition, it may be desirable to introduce a novel restriction sitein the region of the mutation to create cleavage-based detection(Gasparini et al. (1992) Mol. Cell Probes 6:1). It is anticipated thatin certain embodiments amplification may also be performed using Taqligase for amplification (Barany (1991) Proc. Natl. Acad. Sci. USA88:189). In such cases, ligation will occur only if there is a perfectmatch at the 3′ end of the 5′ sequence making it possible to detect thepresence of a known mutation at a specific site by looking for thepresence or absence of amplification.

[0759] The methods described herein may be performed, for example, byutilizing pre-packaged diagnostic kits comprising at least one probenucleic acid or antibody reagent described herein, which may beconveniently used, e.g., in clinical settings to diagnose patientsexhibiting symptoms or family history of a disease or illness involvinga gene encoding a polypeptide of the invention. Furthermore, any celltype or tissue, e.g., preferably peripheral blood leukocytes, in whichthe polypeptide of the invention is expressed may be utilized in theprognostic assays described herein.

[0760] 3. Pharmacogenomics

[0761] Agents, or modulators which have a stimulatory or inhibitoryeffect on activity or expression of a polypeptide of the invention asidentified by a screening assay described herein can be administered toindividuals to treat (prophylactically or therapeutically) disordersassociated with aberrant activity of the polypeptide. In conjunctionwith such treatment, the pharmacogenomics (i.e., the study of therelationship between an individual's genotype and that individual'sresponse to a foreign compound or drug) of the individual may beconsidered. Differences in metabolism of therapeutics can lead to severetoxicity or therapeutic failure by altering the relation between doseand blood concentration of the pharmacologically active drug. Thus, thepharmacogenomics of the individual permits the selection of effectiveagents (e.g., drugs) for prophylactic or therapeutic treatments based ona consideration of the individual's genotype. Such pharmacogenomics canfurther be used to determine appropriate dosages and therapeuticregimens. Accordingly, the activity of a polypeptide of the invention,expression of a nucleic acid of the invention, or mutation content of agene of the invention in an individual can be determined to therebyselect appropriate agent(s) for therapeutic or prophylactic treatment ofthe individual.

[0762] Pharmacogenomics deals with clinically significant hereditaryvariations in the response to drugs due to altered drug disposition andabnormal action in affected persons. See, e.g., Linder (1997) Clin.Chem. 43(2):254-266. In general, two types of pharmacogenetic conditionscan be differentiated. Genetic conditions transmitted as a single factoraltering the way drugs act on the body are referred to as “altered drugaction.” Genetic conditions transmitted as single factors altering theway the body acts on drugs are referred to as “altered drug metabolism”.These pharnacogenetic conditions can occur either as rare defects or aspolymorphisms. For example, glucose-6-phosphate dehydrogenase deficiency(G6PD) is a common inherited enzymopathy in which the main clinicalcomplication is haemolysis after ingestion of oxidant drugs(anti-malarials, sulfonamides, analgesics, nitrofurans) and consumptionof fava beans.

[0763] As an illustrative embodiment, the activity of drug metabolizingenzymes is a major determinant of both the intensity and duration ofdrug action. The discovery of genetic polymorphisms of drug metabolizingenzymes (e.g., N-acetyltransferase 2 (NAT 2) and cytochrome P450 enzymesCYP2D6 and CYP2C19) has provided an explanation as to why some patientsdo not obtain the expected drug effects or show exaggerated drugresponse and serious toxicity after taking the standard and safe dose ofa drug. These polymorphisms are expressed in two phenotypes in thepopulation, the extensive metabolizer (EM) and poor metabolizer (PM).The prevalence of PM is different among different populations. Forexample, the gene coding for CYP2D6 is highly polymorphic and severalmutations have been identified in PM, which all lead to the absence offunctional CYP2D6. Poor metabolizers of CYP2D6 and CYP2C19 quitefrequently experience exaggerated drug response and side effects whenthey receive standard doses. If a metabolite is the active therapeuticmoiety, a PM will show no therapeutic response, as demonstrated for theanalgesic effect of codeine mediated by its CYP2D6-formed metabolitemorphine. The other extreme are the so called ultra-rapid metabolizerswho do not respond to standard doses. Recently, the molecular basis ofultra-rapid metabolism has been identified to be due to CYP2D6 geneamplification.

[0764] Thus, the activity of a polypeptide of the invention, expressionof a nucleic acid encoding the polypeptide, or mutation content of agene encoding the polypeptide in an individual can be determined tothereby select appropriate agent(s) for therapeutic or prophylactictreatment of the individual. In addition, pharmacogenetic studies can beused to apply genotyping of polymorphic alleles encodingdrug-metabolizing enzymes to the identification of an individual's drugresponsiveness phenotype. This knowledge, when applied to dosing or drugselection, can avoid adverse reactions or therapeutic failure and thusenhance therapeutic or prophylactic efficiency when treating a subjectwith a modulator of activity or expression of the polypeptide, such as amodulator identified by one of the exemplary screening assays describedherein.

[0765] 4. Monitoring of Effects During Clinical Trials

[0766] Monitoring the influence of agents (e.g., drugs, compounds) onthe expression or activity of a polypeptide of the invention (e.g., theability to modulate aberrant cell proliferation chemotaxis, and/ordifferentiation) can be applied not only in basic drug screening, butalso in clinical trials. For example, the effectiveness of an agent, asdetermined by a screening assay as described herein, to increase geneexpression, protein levels or protein activity, can be monitored inclinical trials of subjects exhibiting decreased gene expression,protein levels, or protein activity. Alternatively, the effectiveness ofan agent, as determined by a screening assay, to decrease geneexpression, protein levels or protein activity, can be monitored inclinical trials of subjects exhibiting increased gene expression,protein levels, or protein activity. In such clinical trials, expressionor activity of a polypeptide of the invention and preferably, that ofother polypeptide that have been implicated in for example, a cellularproliferation disorder, can be used as a marker of the immuneresponsiveness of a particular cell.

[0767] For example, and not by way of limitation, genes, including thoseof the invention, that are modulated in cells by treatment with an agent(e.g., compound, drug or small molecule) which modulates activity orexpression of a polypeptide of the invention (e.g., as identified in ascreening assay described herein) can be identified. Thus, to study theeffect of agents on cellular proliferation disorders, for example, in aclinical trial, cells can be isolated and RNA prepared and analyzed forthe levels of expression of a gene of the invention and other genesimplicated in the disorder. The levels of gene expression (i.e., a geneexpression pattern) can be quantified by Northern blot analysis orRT-PCR, as described herein, or alternatively by measuring the amount ofprotein produced, by one of the methods as described herein, or bymeasuring the levels of activity of a gene of the invention or othergenes. In this way, the gene expression pattern can serve as a marker,indicative of the physiological response of the cells to the agent.Accordingly, this response state may be determined before, and atvarious points during, treatment of the individual with the agent.

[0768] In a preferred embodiment, the present invention provides amethod for monitoring the effectiveness of treatment of a subject withan agent (e.g., an agonist, antagonist, peptidomimetic, protein,peptide, nucleic acid, small molecule, or other drug candidateidentified by the screening assays described herein) comprising thesteps of (i) obtaining a pre-administration sample from a subject priorto administration of the agent; (ii) detecting he level of thepolypeptide or nucleic acid of the invention in the preadministrationsample; (iii) obtaining one or more post-administration samples from thesubject; (iv) detecting the level the of the polypeptide or nucleic acidof the invention in the post-administration samples; (v) comparing thelevel of the polypeptide or nucleic acid of the invention in thepre-administration sample with the level of the polypeptide or nucleicacid of the invention in the post-administration sample or samples; and(vi) altering the administration of the agent to the subjectaccordingly. For example, increased administration of the agent may bedesirable to increase the expression or activity of the polypeptide tohigher levels than detected, i.e., to increase the effectiveness of theagent. Alternatively, decreased administration of the agent may bedesirable to decrease expression or activity of the polypeptide to lowerlevels than detected, i.e., to decrease the effectiveness of the agent.

[0769] C. Methods of Treatment

[0770] The present invention provides for both prophylactic andtherapeutic methods of treating a subject at risk of (or susceptible to)a disorder or having a disorder associated with aberrant expression oractivity of a polypeptide of the invention, as discussed, for example,in sections above relating to uses of the sequences of the invention.For example, disorders characterized by aberrant expression or activityof the polypeptides of the invention include immunologic disorders,prostate disorders, endothelial cell disorders, developmental disorders,embryonic disorders, and neurological disorders. The nucleic acids,polypeptides, and modulators thereof of the invention can be used totreat immunologic diseases and disorders (e.g., monocyte disorders andplatelet disorders), prostate disorders, embryonic disorders, andneurological disorders, as well as other disorders described herein.

[0771] 1. Prophylactic Methods

[0772] In one aspect, the invention provides a method for preventing ina subject, a disease or condition associated with an aberrant expressionor activity of a polypeptide of the invention, by administering to thesubject an agent which modulates expression or at least one activity ofthe polypeptide. Subjects at risk for a disease which is caused orcontributed to by aberrant expression or activity of a polypeptide ofthe invention can be identified by, for example, any or a combination ofdiagnostic or prognostic assays as described herein. Administration of aprophylactic agent can occur prior to the manifestation of symptomscharacteristic of the aberrancy, such that a disease or disorder isprevented or, alternatively, delayed in its progression. Depending onthe type of aberrancy, for example, an agonist or antagonist agent canbe used for treating the subject.

[0773] The prophylactic agents described herein, for example, can beused to treat a subject at risk of developing disorders such asdisorders discussed for example, in Sections above relative to the usesof the sequences of the invention. For example, an antagonist of anTANGO 239, TANGO 219, TANGO 232, TANGO 281, A236 (INTERCEPT 236), TANGO300, TANGO 353, TANGO 393, TANGO 402, TANGO 351 or TANGO 509 protein maybe used to modulate or treat an immunological disorder. The appropriateagent can be determined based on screening assays described herein.

[0774] 2. Therapeutic Methods

[0775] Another aspect of the invention pertains to methods of modulatingexpression or activity of a polypeptide of the invention for therapeuticpurposes. The modulatory method of the invention involves contacting acell with an agent that modulates one or more of the activities of thepolypeptide. An agent that modulates activity can be an agent asdescribed herein, such as a nucleic acid or a protein, anaturally-occurring cognate ligand of the polypeptide, a peptide, apeptidomimetic, or other small molecule. In one embodiment, the agentstimulates one or more of the biological activities of the polypeptide.Examples of such stimulatory agents include the active polypeptide ofthe invention and a nucleic acid molecule encoding the polypeptide ofthe invention that has been introduced into the cell.

[0776] In another embodiment, the agent inhibits one or more of thebiological activities of the polypeptide of the invention. Examples ofsuch inhibitory agents include antisense nucleic acid molecules andantibodies. These modulatory methods can be performed in vitro (e.g., byculturing the cell with the agent) or, alternatively, in vivo (e.g., byadministering the agent to a subject). As such, the present inventionprovides methods of treating an individual afflicted with a disease ordisorder characterized by aberrant expression or activity of apolypeptide of the invention. In one embodiment, the method involvesadministering an agent (e.g., an agent identified by a screening assaydescribed herein), or combination of agents that modulates (e.g.,upregulates or downregulates) expression or activity. In anotherembodiment, the method involves administering a polypeptide of theinvention or a nucleic acid molecule of the invention as therapy tocompensate for reduced or aberrant expression or activity of thepolypeptide.

[0777] Stimulation of activity is desirable in situations in whichactivity or expression is abnormally low or downregulated and/or inwhich increased activity is likely to have a beneficial effect.Conversely, inhibition of activity is desirable in situations in whichactivity or expression is abnormally high or upregulated and/or in whichdecreased activity is likely to have a beneficial effect.

[0778] This invention is further illustrated by the following exampleswhich should not be construed as limiting. The contents of allreferences, Pat.s and published Pat. applications cited throughout thisapplication are hereby incorporated by reference.

[0779] Deposit of Clones

[0780] A clone encoding human TANGO 239 was deposited on Nov. 20, 1998with the American Type Culture Collection under Accession Number ATCC98999, (also referred to herein as mix EpDHMixl) from which each clonecomprising a particular cDNA clone is obtainable. This deposit is amixture of five strains, each carrying one recombinant plasmid harboringa particular cDNA clone.

[0781] A clone encoding human TANGO 219 (clone EpT219) was depositedwith the American Type Culture Collection (Manassas, Va.) on Sep. 25,1998 as Accession Number 98899, as part of a composite depositrepresenting a mixture of five strains, each carrying one recombinantplasmid harboring a particular cDNA clone.

[0782] A clone containing cDNA molecules encoding human TANGO 281 (cloneEpT 281) was deposited with the American Type Culture Collection, 10801University Boulevard, Manassas, Va., 20110-2209, on Apr. 21, 1999 asAccession Number 207222, as part of a composite deposit representing amixture of strains, each carrying one recombinant plasmid harboring aparticular cDNA clone.

[0783] A clone containing cDNA molecules encoding TANGO 353 (cloneEpT353), was deposited with the American Type Culture Collection(Manassas, Va.) on Jun. 29, 1999 as Accession Number PTA-292, as part ofa composite deposit representing a mixture of three strains, eachcarrying one recombinant plasmid harboring a particular cDNA clone.

[0784] A clone containing cDNA molecules encoding TANGO 393 (cloneEpT393), was deposited with the American Type Culture Collection(Manassas, Va.) on Jun. 29, 1999 as Accession Number PTA-295, as part ofa composite deposit representing a mixture of four strains, eachcarrying one recombinant plasmid harboring a particular cDNA clone.

[0785] A clone containing cDNA molecules encoding TANGO 351 (clone 351),was deposited with the American Type Culture Collection (Manassas, Va.)on Jul. 23, 1999 as Accession Number PTA-424, as part of a compositedeposit representing a mixture of five strains, each carrying onerecombinant plasmid harboring a particular cDNA clone.

[0786] A clone containing cDNA molecules encoding TANGO 509 (509), wasdeposited with the American Type Culture Collection (Manassas, Va.) onJul. 29, 1999 as Accession Number PTA-455, Accession Number PTA-438, andAccession Number PTA-438 respectively, as part of a composite depositrepresenting a mixture of five strains, each carrying one recombinantplasmid harboring a particular cDNA clone.

[0787] To distinguish the strains and isolate a strain harboring aparticular cDNA clone, one can first streak out an aliquot of themixture to single colonies on nutrient medium (e.g., LB plates)supplemented with 100 μg/ml ampicillin, grow single colonies, and thenextract the plasmid DNA using a standard minipreparation procedure.

[0788] A clone containing cDNA molecules encoding TANGO 402 (cloneEpT402), was deposited with the American Type Culture Collection(Manassas, Va.) on Jun. 29, 1999 as Accession Number PTA-294, as part ofa composite deposit representing a mixture of two strains, each carryingone recombinant plasmid harboring a particular cDNA clone.

[0789] One can digest a sample of the DNA minipreparation with acombination of the restriction enzymes Sal I and Not I and resolve theresultant products on a 0.8% agarose gel using standard DNAelectrophoresis conditions. The digest will liberate a fragment asfollows:

[0790] TANGO 239 (EpDH233) 3.0 kb and 3.4 kb

[0791] TANGO 219: 1.3 kb

[0792] TANGO 393 (EpT393): 1.8 kb

[0793] TANGO 353 (EpT353): 1.3 kb

[0794] TANGO 351 (351): 3.4 kb.

[0795] TANGO 509 (509): 3.6 kb

[0796] TANGO 402 (EpT402): 1.4 kb

[0797] The TANGO 281 DNA mini-preparation can be digested with acombination of the restriction enzymes SalI, NotI, XbaI and EcorV andthe resultant products resolved on a 0.8% agarose gel using standard DNAelectrophoresis conditions. The digest liberates fragments as follows:

[0798] Human TANGO 281 (clone EpT281): 0.9 kb and 0.9 kb (human TANGO281 Has an XbaI cut site at about bp 900).

[0799] The identity of each of the strains can be inferred from the DNAfragments liberated.

[0800] All publications, Pat.s and Pat. applications mentioned in thisspecification are herein incorporated by reference into thespecification to the same extent as if each individual publication, Pat.or Pat. application was specifically and individually indicated to beincorporated herein by reference.

[0801] Equivalents

[0802] Those skilled in the art will recognize, or be able to ascertainusing no more than routine experimentation, many equivalents to thespecific embodiments of the invention described herein. Such equivalentsare intended to be encompassed by the following claims.

0 SEQUENCE LISTING <160> NUMBER OF SEQ ID NOS: 50 <210> SEQ ID NO 1<211> LENGTH: 3413 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220>FEATURE: <221> NAME/KEY: CDS <222> LOCATION: (344)...(1990) <400>SEQUENCE: 1 gtcgacccac gcgtcccggg ctggcctttc aaagtgtgca gttgtctcctccctgtccag 60 ccccatcgtc gcccaggacc agctgggccg cggtctgacc tgaggctgctgctcagcgcc 120 ggggcgctgg cgctctccat tcgagcacct tccagcatac cgctcggctccgggagccgc 180 tctgcaaagt tgggcagctc agagcgcaag ctttgcctct cgacttctccctccttgggt 240 ccccggcgcc cccgcctccc acgatccctt tcactaggag cagccagtcccagcgggctg 300 gcaacttgca ccccttccta gtcatcctcc ctgaaacgcg acc atg ctgtta agg 355 Met Leu Leu Arg 1 ggc gtc ctc ctg gcg ttg caa gcc ctg cagctc gcc ggt gcc ctc gac 403 Gly Val Leu Leu Ala Leu Gln Ala Leu Gln LeuAla Gly Ala Leu Asp 5 10 15 20 ctg ccc gct ggg tcc tgt gcc ttt gaa gagagc act tgc ggc ttt gac 451 Leu Pro Ala Gly Ser Cys Ala Phe Glu Glu SerThr Cys Gly Phe Asp 25 30 35 tcc gtg ttg gcc tct ctg ccg tgg att tta aatgag gaa ggc cat tac 499 Ser Val Leu Ala Ser Leu Pro Trp Ile Leu Asn GluGlu Gly His Tyr 40 45 50 att tat gtg gat acc tcc ttt ggc aag cag ggg gagaaa gct gtg ctg 547 Ile Tyr Val Asp Thr Ser Phe Gly Lys Gln Gly Glu LysAla Val Leu 55 60 65 cta agt cct gac tta cag gct gag gaa tgg agc tgc ctccgt ttg gtc 595 Leu Ser Pro Asp Leu Gln Ala Glu Glu Trp Ser Cys Leu ArgLeu Val 70 75 80 tac cag ata acc aca tct tcg gag tct ctg tca gat ccc agccag ctg 643 Tyr Gln Ile Thr Thr Ser Ser Glu Ser Leu Ser Asp Pro Ser GlnLeu 85 90 95 100 aac ctc tac atg aga ttt gaa gat gaa agc ttt gat cgc ttgctt tgg 691 Asn Leu Tyr Met Arg Phe Glu Asp Glu Ser Phe Asp Arg Leu LeuTrp 105 110 115 tca gct aag gaa cct tca gac agc tgg ctc ata gcc agc ttggat ttg 739 Ser Ala Lys Glu Pro Ser Asp Ser Trp Leu Ile Ala Ser Leu AspLeu 120 125 130 caa aac agt tcc aag aaa ttc aag att tta ata gaa ggt gtacta gga 787 Gln Asn Ser Ser Lys Lys Phe Lys Ile Leu Ile Glu Gly Val LeuGly 135 140 145 cag gga aac aca gcc agc atc gca cta ttt gaa atc aag atgaca acc 835 Gln Gly Asn Thr Ala Ser Ile Ala Leu Phe Glu Ile Lys Met ThrThr 150 155 160 ggc tac tgt att gaa tgt gac ttt gaa gaa aat cat ctc tgtggc ttt 883 Gly Tyr Cys Ile Glu Cys Asp Phe Glu Glu Asn His Leu Cys GlyPhe 165 170 175 180 gtg aac cgc tgg aat ccc aat gtg aac tgg ttt gtt ggagga gga agt 931 Val Asn Arg Trp Asn Pro Asn Val Asn Trp Phe Val Gly GlyGly Ser 185 190 195 att cgg aat gtc cac tcc att ctc cca cag gat cac accttc aag agt 979 Ile Arg Asn Val His Ser Ile Leu Pro Gln Asp His Thr PheLys Ser 200 205 210 gaa ctg ggc cac tac atg tac gtg gac tca gtt tat gtgaag cac ttc 1027 Glu Leu Gly His Tyr Met Tyr Val Asp Ser Val Tyr Val LysHis Phe 215 220 225 cag gag gtg gca cag ctc atc tcc ccg ttg acc acg gccccc atg gct 1075 Gln Glu Val Ala Gln Leu Ile Ser Pro Leu Thr Thr Ala ProMet Ala 230 235 240 ggc tgc ctg tca ttt tat tac cag atc cag cag ggg aatgac aat gtc 1123 Gly Cys Leu Ser Phe Tyr Tyr Gln Ile Gln Gln Gly Asn AspAsn Val 245 250 255 260 ttt tcc ctt tac act cgg gat gtg gct ggc ctt tacgag gaa atc tgg 1171 Phe Ser Leu Tyr Thr Arg Asp Val Ala Gly Leu Tyr GluGlu Ile Trp 265 270 275 aaa gca gac agg cca ggg aat gct gcc tgg aac cttgcg gag gtc gag 1219 Lys Ala Asp Arg Pro Gly Asn Ala Ala Trp Asn Leu AlaGlu Val Glu 280 285 290 ttc aat gct cct tac ccc atg gag gtt att ttt gaagtt gct ttc aat 1267 Phe Asn Ala Pro Tyr Pro Met Glu Val Ile Phe Glu ValAla Phe Asn 295 300 305 ggt ccc aag gga ggt tat gtt gcc ctg gat gat atttca ttc tct cct 1315 Gly Pro Lys Gly Gly Tyr Val Ala Leu Asp Asp Ile SerPhe Ser Pro 310 315 320 gtt cac tgc cag aat cag aca gaa ctt ctg ttc agtgcc gtg gaa gcc 1363 Val His Cys Gln Asn Gln Thr Glu Leu Leu Phe Ser AlaVal Glu Ala 325 330 335 340 agc tgc aat ttt gag caa gat ctc tgc aac ttttac caa gat aaa gaa 1411 Ser Cys Asn Phe Glu Gln Asp Leu Cys Asn Phe TyrGln Asp Lys Glu 345 350 355 ggt cca ggt tgg acc cga gtg aaa gta aaa ccaaac atg tat cgg gct 1459 Gly Pro Gly Trp Thr Arg Val Lys Val Lys Pro AsnMet Tyr Arg Ala 360 365 370 gga gac cac act aca ggc tta ggg tat tac ctgcta gcc aac aca aag 1507 Gly Asp His Thr Thr Gly Leu Gly Tyr Tyr Leu LeuAla Asn Thr Lys 375 380 385 ttc aca tct cag cct ggc tac att gga agg ctctat ggg ccc tcc cta 1555 Phe Thr Ser Gln Pro Gly Tyr Ile Gly Arg Leu TyrGly Pro Ser Leu 390 395 400 cca gga aac ttg cag tat tgt ctg cgt ttt cattat gcc atc tat gga 1603 Pro Gly Asn Leu Gln Tyr Cys Leu Arg Phe His TyrAla Ile Tyr Gly 405 410 415 420 ttt tta aaa atg agt gac acc cta gca gtttac atc ttt gaa gag aac 1651 Phe Leu Lys Met Ser Asp Thr Leu Ala Val TyrIle Phe Glu Glu Asn 425 430 435 cat gtg gtt caa gag aag atc tgg tct gtgttg gag tcc cca agg ggt 1699 His Val Val Gln Glu Lys Ile Trp Ser Val LeuGlu Ser Pro Arg Gly 440 445 450 gtt tgg atg caa gct gaa atc acc ttt aagaag ccc atg cct acc aag 1747 Val Trp Met Gln Ala Glu Ile Thr Phe Lys LysPro Met Pro Thr Lys 455 460 465 gtg gtt ttc atg agc cta tgc aaa agt ttctgg gac tgt ggg ctt gta 1795 Val Val Phe Met Ser Leu Cys Lys Ser Phe TrpAsp Cys Gly Leu Val 470 475 480 gcc ctg gat gac att aca ata caa ttg ggaagc tgc tca tct tca gag 1843 Ala Leu Asp Asp Ile Thr Ile Gln Leu Gly SerCys Ser Ser Ser Glu 485 490 495 500 aaa ctt cca cct cac ctg gag agt gtactt tcg agc aag atg aat gta 1891 Lys Leu Pro Pro His Leu Glu Ser Val LeuSer Ser Lys Met Asn Val 505 510 515 cat tta ctc agg aga aaa gaa acc ggagca gct ggc aca gga gga ggg 1939 His Leu Leu Arg Arg Lys Glu Thr Gly AlaAla Gly Thr Gly Gly Gly 520 525 530 gag aaa ctc cca ctt cct aca cag gaccaa agg gag atc aca cta ctg 1987 Glu Lys Leu Pro Leu Pro Thr Gln Asp GlnArg Glu Ile Thr Leu Leu 535 540 545 ggg taggctacta catgtacatt gaggcctcccatatggtgta tggacaaaaa 2040 Gly gcacgcctct tgtccaggcc tctgcgaggagtctctggaa aacactgctt gacctttttc 2100 taccacatgt atggaggggg cactggcctgctgagtgttt atctgaaaaa ggaagaagac 2160 agtgaagagt ccctcttatg gaggagaagaggtgaacaga gcatttcctg gctacgagca 2220 ctgattgaat acagctgtga gaggcaacaccagataattt ttgaagccat tcgaggagta 2280 tcaataagaa gtgatattgc cattgatgatgttaaatttc aggcaggacc ctgtggagaa 2340 atggaagata caactcaaca atcatcaggatattctgagg acttaaatga aattgagtat 2400 taagaaatga tctgcattgg atttactagacgaaaaccat acctctcttc aatcaaaatg 2460 aaaacaaagc aaatgaatac tggacagtcttaacaatttt ataagttata aaatgacttt 2520 agagcaccct ccttcattac ttttgcaaaaacatactgac tcagggctct ttttttcttt 2580 ttgcatatga caactgttac tagaaatacaggctactggt tttgcataga tcattcatct 2640 taattttggt accagttaaa aatacaaatgtactatattg tagtcatttt aaagtacaca 2700 aagggcacaa tcaaaatgag atgcactcatttaaatctgc attcagtgaa tgtattggga 2760 gaaaaatagg tcttgcaggt ttccttttgaattttaagta tcataaatat tttttaagta 2820 aataatacgg ggtgtcagta atatctgcagaatgaatgca gtctttcatg ctaatgagtt 2880 agtctggaaa aataaagtct tattttctatgttttattca tagaaatgga gtattaattt 2940 ttaatatttt caccatatgt gataacaaaggatctttcat gaatgtccaa gggtaagtca 3000 gtattaatta atgctgtatt acaaggcaatgctaccttct ttattccccc tttgaactac 3060 ctttgaagtc actatgagca catggatagaaatttaactt ttttttgtaa agcaagctta 3120 aaatgtttat gtatacatac ccagcaacttttataaatgt gttaaacaat tttactgatt 3180 tttataataa atattttggt aagattttgaataatatgaa ttcaggcaga tatactaaac 3240 tgcttttatt tacttgttta gaaaattgtatatatatgtt tgtgtatcct aacagctgct 3300 atgaaattat aaaattacct aataaaaataatttgaaaat caaaaaaaaa aaaaaaaaaa 3360 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaaaaaaaaaaaa aaaaaagggg ggg 3413 <210> SEQ ID NO 2 <211> LENGTH: 549 <212>TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 2 Met Leu Leu ArgGly Val Leu Leu Ala Leu Gln Ala Leu Gln Leu Ala 1 5 10 15 Gly Ala LeuAsp Leu Pro Ala Gly Ser Cys Ala Phe Glu Glu Ser Thr 20 25 30 Cys Gly PheAsp Ser Val Leu Ala Ser Leu Pro Trp Ile Leu Asn Glu 35 40 45 Glu Gly HisTyr Ile Tyr Val Asp Thr Ser Phe Gly Lys Gln Gly Glu 50 55 60 Lys Ala ValLeu Leu Ser Pro Asp Leu Gln Ala Glu Glu Trp Ser Cys 65 70 75 80 Leu ArgLeu Val Tyr Gln Ile Thr Thr Ser Ser Glu Ser Leu Ser Asp 85 90 95 Pro SerGln Leu Asn Leu Tyr Met Arg Phe Glu Asp Glu Ser Phe Asp 100 105 110 ArgLeu Leu Trp Ser Ala Lys Glu Pro Ser Asp Ser Trp Leu Ile Ala 115 120 125Ser Leu Asp Leu Gln Asn Ser Ser Lys Lys Phe Lys Ile Leu Ile Glu 130 135140 Gly Val Leu Gly Gln Gly Asn Thr Ala Ser Ile Ala Leu Phe Glu Ile 145150 155 160 Lys Met Thr Thr Gly Tyr Cys Ile Glu Cys Asp Phe Glu Glu AsnHis 165 170 175 Leu Cys Gly Phe Val Asn Arg Trp Asn Pro Asn Val Asn TrpPhe Val 180 185 190 Gly Gly Gly Ser Ile Arg Asn Val His Ser Ile Leu ProGln Asp His 195 200 205 Thr Phe Lys Ser Glu Leu Gly His Tyr Met Tyr ValAsp Ser Val Tyr 210 215 220 Val Lys His Phe Gln Glu Val Ala Gln Leu IleSer Pro Leu Thr Thr 225 230 235 240 Ala Pro Met Ala Gly Cys Leu Ser PheTyr Tyr Gln Ile Gln Gln Gly 245 250 255 Asn Asp Asn Val Phe Ser Leu TyrThr Arg Asp Val Ala Gly Leu Tyr 260 265 270 Glu Glu Ile Trp Lys Ala AspArg Pro Gly Asn Ala Ala Trp Asn Leu 275 280 285 Ala Glu Val Glu Phe AsnAla Pro Tyr Pro Met Glu Val Ile Phe Glu 290 295 300 Val Ala Phe Asn GlyPro Lys Gly Gly Tyr Val Ala Leu Asp Asp Ile 305 310 315 320 Ser Phe SerPro Val His Cys Gln Asn Gln Thr Glu Leu Leu Phe Ser 325 330 335 Ala ValGlu Ala Ser Cys Asn Phe Glu Gln Asp Leu Cys Asn Phe Tyr 340 345 350 GlnAsp Lys Glu Gly Pro Gly Trp Thr Arg Val Lys Val Lys Pro Asn 355 360 365Met Tyr Arg Ala Gly Asp His Thr Thr Gly Leu Gly Tyr Tyr Leu Leu 370 375380 Ala Asn Thr Lys Phe Thr Ser Gln Pro Gly Tyr Ile Gly Arg Leu Tyr 385390 395 400 Gly Pro Ser Leu Pro Gly Asn Leu Gln Tyr Cys Leu Arg Phe HisTyr 405 410 415 Ala Ile Tyr Gly Phe Leu Lys Met Ser Asp Thr Leu Ala ValTyr Ile 420 425 430 Phe Glu Glu Asn His Val Val Gln Glu Lys Ile Trp SerVal Leu Glu 435 440 445 Ser Pro Arg Gly Val Trp Met Gln Ala Glu Ile ThrPhe Lys Lys Pro 450 455 460 Met Pro Thr Lys Val Val Phe Met Ser Leu CysLys Ser Phe Trp Asp 465 470 475 480 Cys Gly Leu Val Ala Leu Asp Asp IleThr Ile Gln Leu Gly Ser Cys 485 490 495 Ser Ser Ser Glu Lys Leu Pro ProHis Leu Glu Ser Val Leu Ser Ser 500 505 510 Lys Met Asn Val His Leu LeuArg Arg Lys Glu Thr Gly Ala Ala Gly 515 520 525 Thr Gly Gly Gly Glu LysLeu Pro Leu Pro Thr Gln Asp Gln Arg Glu 530 535 540 Ile Thr Leu Leu Gly545 <210> SEQ ID NO 3 <211> LENGTH: 3413 <212> TYPE: DNA <213> ORGANISM:Homo sapiens <220> FEATURE: <221> NAME/KEY: CDS <222> LOCATION:(344)...(2401) <400> SEQUENCE: 3 gtcgacccac gcgtcccggg ctggcctttcaaagtgtgca gttgtctcct ccctgtccag 60 ccccatcgtc gcccaggacc agctgggccgcggtctgacc tgaggctgct gctcagcgcc 120 ggggcgctgg cgctctccat tcgagcaccttccagcatac cgctcggctc cgggagccgc 180 tctgcaaagt tgggcagctc agagcgcaagctttgcctct cgacttctcc ctccttgggt 240 ccccggcgcc cccgcctccc acgatccctttcactaggag cagccagtcc cagcgggctg 300 gcaacttgca ccccttccta gtcatcctccctgaaacgcg acc atg ctg tta agg 355 Met Leu Leu Arg 1 ggc gtc ctc ctg gcgttg caa gcc ctg cag ctc gcc ggt gcc ctc gac 403 Gly Val Leu Leu Ala LeuGln Ala Leu Gln Leu Ala Gly Ala Leu Asp 5 10 15 20 ctg ccc gct ggg tcctgt gcc ttt gaa gag agc act tgc ggc ttt gac 451 Leu Pro Ala Gly Ser CysAla Phe Glu Glu Ser Thr Cys Gly Phe Asp 25 30 35 tcc gtg ttg gcc tct ctgccg tgg att tta aat gag gaa ggc cat tac 499 Ser Val Leu Ala Ser Leu ProTrp Ile Leu Asn Glu Glu Gly His Tyr 40 45 50 att tat gtg gat acc tcc tttggc aag cag ggg gag aaa gct gtg ctg 547 Ile Tyr Val Asp Thr Ser Phe GlyLys Gln Gly Glu Lys Ala Val Leu 55 60 65 cta agt cct gac tta cag gct gaggaa tgg agc tgc ctc cgt ttg gtc 595 Leu Ser Pro Asp Leu Gln Ala Glu GluTrp Ser Cys Leu Arg Leu Val 70 75 80 tac cag ata acc aca tct tcg gag tctctg tca gat ccc agc cag ctg 643 Tyr Gln Ile Thr Thr Ser Ser Glu Ser LeuSer Asp Pro Ser Gln Leu 85 90 95 100 aac ctc tac atg aga ttt gaa gat gaaagc ttt gat cgc ttg ctt tgg 691 Asn Leu Tyr Met Arg Phe Glu Asp Glu SerPhe Asp Arg Leu Leu Trp 105 110 115 tca gct aag gaa cct tca gac agc tggctc ata gcc agc ttg gat ttg 739 Ser Ala Lys Glu Pro Ser Asp Ser Trp LeuIle Ala Ser Leu Asp Leu 120 125 130 caa aac agt tcc aag aaa ttc aag atttta ata gaa ggt gta cta gga 787 Gln Asn Ser Ser Lys Lys Phe Lys Ile LeuIle Glu Gly Val Leu Gly 135 140 145 cag gga aac aca gcc agc atc gca ctattt gaa atc aag atg aca acc 835 Gln Gly Asn Thr Ala Ser Ile Ala Leu PheGlu Ile Lys Met Thr Thr 150 155 160 ggc tac tgt att gaa tgt gac ttt gaagaa aat cat ctc tgt ggc ttt 883 Gly Tyr Cys Ile Glu Cys Asp Phe Glu GluAsn His Leu Cys Gly Phe 165 170 175 180 gtg aac cgc tgg aat ccc aat gtgaac tgg ttt gtt gga gga gga agt 931 Val Asn Arg Trp Asn Pro Asn Val AsnTrp Phe Val Gly Gly Gly Ser 185 190 195 att cgg aat gtc cac tcc att ctccca cag gat cac acc ttc aag agt 979 Ile Arg Asn Val His Ser Ile Leu ProGln Asp His Thr Phe Lys Ser 200 205 210 gaa ctg ggc cac tac atg tac gtggac tca gtt tat gtg aag cac ttc 1027 Glu Leu Gly His Tyr Met Tyr Val AspSer Val Tyr Val Lys His Phe 215 220 225 cag gag gtg gca cag ctc atc tccccg ttg acc acg gcc ccc atg gct 1075 Gln Glu Val Ala Gln Leu Ile Ser ProLeu Thr Thr Ala Pro Met Ala 230 235 240 ggc tgc ctg tca ttt tat tac cagatc cag cag ggg aat gac aat gtc 1123 Gly Cys Leu Ser Phe Tyr Tyr Gln IleGln Gln Gly Asn Asp Asn Val 245 250 255 260 ttt tcc ctt tac act cgg gatgtg gct ggc ctt tac gag gaa atc tgg 1171 Phe Ser Leu Tyr Thr Arg Asp ValAla Gly Leu Tyr Glu Glu Ile Trp 265 270 275 aaa gca gac agg cca ggg aatgct gcc tgg aac ctt gcg gag gtc gag 1219 Lys Ala Asp Arg Pro Gly Asn AlaAla Trp Asn Leu Ala Glu Val Glu 280 285 290 ttc aat gct cct tac ccc atggag gtt att ttt gaa gtt gct ttc aat 1267 Phe Asn Ala Pro Tyr Pro Met GluVal Ile Phe Glu Val Ala Phe Asn 295 300 305 ggt ccc aag gga ggt tat gttgcc ctg gat gat att tca ttc tct cct 1315 Gly Pro Lys Gly Gly Tyr Val AlaLeu Asp Asp Ile Ser Phe Ser Pro 310 315 320 gtt cac tgc cag aat cag acagaa ctt ctg ttc agt gcc gtg gaa gcc 1363 Val His Cys Gln Asn Gln Thr GluLeu Leu Phe Ser Ala Val Glu Ala 325 330 335 340 agc tgc aat ttt gag caagat ctc tgc aac ttt tac caa gat aaa gaa 1411 Ser Cys Asn Phe Glu Gln AspLeu Cys Asn Phe Tyr Gln Asp Lys Glu 345 350 355 ggt cca ggt tgg acc cgagtg aaa gta aaa cca aac atg tat cgg gct 1459 Gly Pro Gly Trp Thr Arg ValLys Val Lys Pro Asn Met Tyr Arg Ala 360 365 370 gga gac cac act aca ggctta ggg tat tac ctg cta gcc aac aca aag 1507 Gly Asp His Thr Thr Gly LeuGly Tyr Tyr Leu Leu Ala Asn Thr Lys 375 380 385 ttc aca tct cag cct ggctac att gga agg ctc tat ggg ccc tcc cta 1555 Phe Thr Ser Gln Pro Gly TyrIle Gly Arg Leu Tyr Gly Pro Ser Leu 390 395 400 cca gga aac ttg cag tattgt ctg cgt ttt cat tat gcc atc tat gga 1603 Pro Gly Asn Leu Gln Tyr CysLeu Arg Phe His Tyr Ala Ile Tyr Gly 405 410 415 420 ttt tta aaa atg agtgac acc cta gca gtt tac atc ttt gaa gag aac 1651 Phe Leu Lys Met Ser AspThr Leu Ala Val Tyr Ile Phe Glu Glu Asn 425 430 435 cat gtg gtt caa gagaag atc tgg tct gtg ttg gag tcc cca agg ggt 1699 His Val Val Gln Glu LysIle Trp Ser Val Leu Glu Ser Pro Arg Gly 440 445 450 gtt tgg atg caa gctgaa atc acc ttt aag aag ccc atg cct acc aag 1747 Val Trp Met Gln Ala GluIle Thr Phe Lys Lys Pro Met Pro Thr Lys 455 460 465 gtg gtt ttc atg agccta tgc aaa agt ttc tgg gac tgt ggg ctt gta 1795 Val Val Phe Met Ser LeuCys Lys Ser Phe Trp Asp Cys Gly Leu Val 470 475 480 gcc ctg gat gac attaca ata caa ttg gga agc tgc tca tct tca gag 1843 Ala Leu Asp Asp Ile ThrIle Gln Leu Gly Ser Cys Ser Ser Ser Glu 485 490 495 500 aaa ctt cca ccctca cct gga gag tgt act ttc gag caa gat gaa tgt 1891 Lys Leu Pro Pro SerPro Gly Glu Cys Thr Phe Glu Gln Asp Glu Cys 505 510 515 aca ttt act caggag aaa aga aac cgg agc agc tgg cac agg agg agg 1939 Thr Phe Thr Gln GluLys Arg Asn Arg Ser Ser Trp His Arg Arg Arg 520 525 530 gga gaa act cccact tcc tac aca gga cca aag gga gat cac act act 1987 Gly Glu Thr Pro ThrSer Tyr Thr Gly Pro Lys Gly Asp His Thr Thr 535 540 545 ggg gta ggc tactac atg tac att gag gcc tcc cat atg gtg tat gga 2035 Gly Val Gly Tyr TyrMet Tyr Ile Glu Ala Ser His Met Val Tyr Gly 550 555 560 caa aaa gca cgcctc ttg tcc agg cct ctg cga gga gtc tct gga aaa 2083 Gln Lys Ala Arg LeuLeu Ser Arg Pro Leu Arg Gly Val Ser Gly Lys 565 570 575 580 cac tgc ttgacc ttt ttc tac cac atg tat gga ggg ggc act ggc ctg 2131 His Cys Leu ThrPhe Phe Tyr His Met Tyr Gly Gly Gly Thr Gly Leu 585 590 595 ctg agt gtttat ctg aaa aag gaa gaa gac agt gaa gag tcc ctc tta 2179 Leu Ser Val TyrLeu Lys Lys Glu Glu Asp Ser Glu Glu Ser Leu Leu 600 605 610 tgg agg agaaga ggt gaa cag agc att tcc tgg cta cga gca ctg att 2227 Trp Arg Arg ArgGly Glu Gln Ser Ile Ser Trp Leu Arg Ala Leu Ile 615 620 625 gaa tac agctgt gag agg caa cac cag ata att ttt gaa gcc att cga 2275 Glu Tyr Ser CysGlu Arg Gln His Gln Ile Ile Phe Glu Ala Ile Arg 630 635 640 gga gta tcaata aga agt gat att gcc att gat gat gtt aaa ttt cag 2323 Gly Val Ser IleArg Ser Asp Ile Ala Ile Asp Asp Val Lys Phe Gln 645 650 655 660 gca ggaccc tgt gga gaa atg gaa gat aca act caa caa tca tca gga 2371 Ala Gly ProCys Gly Glu Met Glu Asp Thr Thr Gln Gln Ser Ser Gly 665 670 675 tat tctgag gac tta aat gaa att gag tat taagaaatga tctgcattgg 2421 Tyr Ser GluAsp Leu Asn Glu Ile Glu Tyr 680 685 atttactaga cgaaaaccat acctctcttcaatcaaaatg aaaacaaagc aaatgaatac 2481 tggacagtct taacaatttt ataagttataaaatgacttt agagcaccct ccttcattac 2541 ttttgcaaaa acatactgac tcagggctctttttttcttt ttgcatatga caactgttac 2601 tagaaataca ggctactggt tttgcatagatcattcatct taattttggt accagttaaa 2661 aatacaaatg tactatattg tagtcattttaaagtacaca aagggcacaa tcaaaatgag 2721 atgcactcat ttaaatctgc attcagtgaatgtattggga gaaaaatagg tcttgcaggt 2781 ttccttttga attttaagta tcataaatattttttaagta aataatacgg ggtgtcagta 2841 atatctgcag aatgaatgca gtctttcatgctaatgagtt agtctggaaa aataaagtct 2901 tattttctat gttttattca tagaaatggagtattaattt ttaatatttt caccatatgt 2961 gataacaaag gatctttcat gaatgtccaagggtaagtca gtattaatta atgctgtatt 3021 acaaggcaat gctaccttct ttattccccctttgaactac ctttgaagtc actatgagca 3081 catggataga aatttaactt ttttttgtaaagcaagctta aaatgtttat gtatacatac 3141 ccagcaactt ttataaatgt gttaaacaattttactgatt tttataataa atattttggt 3201 aagattttga ataatatgaa ttcaggcagatatactaaac tgcttttatt tacttgttta 3261 gaaaattgta tatatatgtt tgtgtatcctaacagctgct atgaaattat aaaattacct 3321 aataaaaata atttgaaaat caaaaaaaaaaaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 3381 aaaaaaaaaa aaaaaaaaaa aaaaaagggggg 3413 <210> SEQ ID NO 4 <211> LENGTH: 686 <212> TYPE: PRT <213>ORGANISM: Homo sapiens <400> SEQUENCE: 4 Met Leu Leu Arg Gly Val Leu LeuAla Leu Gln Ala Leu Gln Leu Ala 1 5 10 15 Gly Ala Leu Asp Leu Pro AlaGly Ser Cys Ala Phe Glu Glu Ser Thr 20 25 30 Cys Gly Phe Asp Ser Val LeuAla Ser Leu Pro Trp Ile Leu Asn Glu 35 40 45 Glu Gly His Tyr Ile Tyr ValAsp Thr Ser Phe Gly Lys Gln Gly Glu 50 55 60 Lys Ala Val Leu Leu Ser ProAsp Leu Gln Ala Glu Glu Trp Ser Cys 65 70 75 80 Leu Arg Leu Val Tyr GlnIle Thr Thr Ser Ser Glu Ser Leu Ser Asp 85 90 95 Pro Ser Gln Leu Asn LeuTyr Met Arg Phe Glu Asp Glu Ser Phe Asp 100 105 110 Arg Leu Leu Trp SerAla Lys Glu Pro Ser Asp Ser Trp Leu Ile Ala 115 120 125 Ser Leu Asp LeuGln Asn Ser Ser Lys Lys Phe Lys Ile Leu Ile Glu 130 135 140 Gly Val LeuGly Gln Gly Asn Thr Ala Ser Ile Ala Leu Phe Glu Ile 145 150 155 160 LysMet Thr Thr Gly Tyr Cys Ile Glu Cys Asp Phe Glu Glu Asn His 165 170 175Leu Cys Gly Phe Val Asn Arg Trp Asn Pro Asn Val Asn Trp Phe Val 180 185190 Gly Gly Gly Ser Ile Arg Asn Val His Ser Ile Leu Pro Gln Asp His 195200 205 Thr Phe Lys Ser Glu Leu Gly His Tyr Met Tyr Val Asp Ser Val Tyr210 215 220 Val Lys His Phe Gln Glu Val Ala Gln Leu Ile Ser Pro Leu ThrThr 225 230 235 240 Ala Pro Met Ala Gly Cys Leu Ser Phe Tyr Tyr Gln IleGln Gln Gly 245 250 255 Asn Asp Asn Val Phe Ser Leu Tyr Thr Arg Asp ValAla Gly Leu Tyr 260 265 270 Glu Glu Ile Trp Lys Ala Asp Arg Pro Gly AsnAla Ala Trp Asn Leu 275 280 285 Ala Glu Val Glu Phe Asn Ala Pro Tyr ProMet Glu Val Ile Phe Glu 290 295 300 Val Ala Phe Asn Gly Pro Lys Gly GlyTyr Val Ala Leu Asp Asp Ile 305 310 315 320 Ser Phe Ser Pro Val His CysGln Asn Gln Thr Glu Leu Leu Phe Ser 325 330 335 Ala Val Glu Ala Ser CysAsn Phe Glu Gln Asp Leu Cys Asn Phe Tyr 340 345 350 Gln Asp Lys Glu GlyPro Gly Trp Thr Arg Val Lys Val Lys Pro Asn 355 360 365 Met Tyr Arg AlaGly Asp His Thr Thr Gly Leu Gly Tyr Tyr Leu Leu 370 375 380 Ala Asn ThrLys Phe Thr Ser Gln Pro Gly Tyr Ile Gly Arg Leu Tyr 385 390 395 400 GlyPro Ser Leu Pro Gly Asn Leu Gln Tyr Cys Leu Arg Phe His Tyr 405 410 415Ala Ile Tyr Gly Phe Leu Lys Met Ser Asp Thr Leu Ala Val Tyr Ile 420 425430 Phe Glu Glu Asn His Val Val Gln Glu Lys Ile Trp Ser Val Leu Glu 435440 445 Ser Pro Arg Gly Val Trp Met Gln Ala Glu Ile Thr Phe Lys Lys Pro450 455 460 Met Pro Thr Lys Val Val Phe Met Ser Leu Cys Lys Ser Phe TrpAsp 465 470 475 480 Cys Gly Leu Val Ala Leu Asp Asp Ile Thr Ile Gln LeuGly Ser Cys 485 490 495 Ser Ser Ser Glu Lys Leu Pro Pro Ser Pro Gly GluCys Thr Phe Glu 500 505 510 Gln Asp Glu Cys Thr Phe Thr Gln Glu Lys ArgAsn Arg Ser Ser Trp 515 520 525 His Arg Arg Arg Gly Glu Thr Pro Thr SerTyr Thr Gly Pro Lys Gly 530 535 540 Asp His Thr Thr Gly Val Gly Tyr TyrMet Tyr Ile Glu Ala Ser His 545 550 555 560 Met Val Tyr Gly Gln Lys AlaArg Leu Leu Ser Arg Pro Leu Arg Gly 565 570 575 Val Ser Gly Lys His CysLeu Thr Phe Phe Tyr His Met Tyr Gly Gly 580 585 590 Gly Thr Gly Leu LeuSer Val Tyr Leu Lys Lys Glu Glu Asp Ser Glu 595 600 605 Glu Ser Leu LeuTrp Arg Arg Arg Gly Glu Gln Ser Ile Ser Trp Leu 610 615 620 Arg Ala LeuIle Glu Tyr Ser Cys Glu Arg Gln His Gln Ile Ile Phe 625 630 635 640 GluAla Ile Arg Gly Val Ser Ile Arg Ser Asp Ile Ala Ile Asp Asp 645 650 655Val Lys Phe Gln Ala Gly Pro Cys Gly Glu Met Glu Asp Thr Thr Gln 660 665670 Gln Ser Ser Gly Tyr Ser Glu Asp Leu Asn Glu Ile Glu Tyr 675 680 685<210> SEQ ID NO 5 <211> LENGTH: 1029 <212> TYPE: DNA <213> ORGANISM:Homo sapiens <220> FEATURE: <221> NAME/KEY: CDS <222> LOCATION:(209)...(370) <400> SEQUENCE: 5 gtcgacccac gcgtccgccg ggctacgagtggccggacgc tacagccttg cgcagcgcgc 60 tctgctcctc agactcttcg aatttgagcagcctgtggca tcccccagca ggtcccccag 120 ctccttgcct agcaccctcc cttccctaggagcagcgggc cacagtgagc cagcagccct 180 cgcgggtcct cctgcctgaa gttcaact atgcta cta gaa ggg gtc ctg ctg 232 Met Leu Leu Glu Gly Val Leu Leu 1 5 gtagtg caa gcc ttg cag ctt gcc aat gcc cta gac ctg ccc gct ggc 280 Val ValGln Ala Leu Gln Leu Ala Asn Ala Leu Asp Leu Pro Ala Gly 10 15 20 tcc tgcgcc ttt gaa gaa gac acg tgt ggc ttt gac tcc gtg ttt gcg 328 Ser Cys AlaPhe Glu Glu Asp Thr Cys Gly Phe Asp Ser Val Phe Ala 25 30 35 40 ttt ctgcct tgg ata cta aat gag gaa ggt aag ggg act tcg 370 Phe Leu Pro Trp IleLeu Asn Glu Glu Gly Lys Gly Thr Ser 45 50 tagaaagatg ctcgaggtgaactttcttca cgtcttgttc ctcccaaccc cccggaagta 430 aagatatctt ggagttacttccctttggga ggaaaagtgt gtgagtcatg aaacctcctt 490 ccaactctcc tgcagcaaagagtggccagg gaaaccacgg gaaagggggc ggaggggaac 550 agctgtgtac ctggctctgagcatgcgctc ctacccccag cacaccctat tgaaagggac 610 aaaggggatt ctgctaatgattgttgcccc tagccgtgtg ccccctgcag gctgatagcc 670 ttgctagtct cagtggctacttgcccgagc tgagattgtc aaacggacta gctcacagga 730 agctttgcag aaattttccacacggttgtg agcgtcctct gtgctaagct ctcccacttt 790 ggtccaccca cagcagttttacctgtgatt catcctttcc cattgtatct aattcagcac 850 tggacaaaag agttaactccaccacggagt ccctgaagcc actgggctag ggccaattga 910 tcagtcacat tactctgcaccgctggggtt ccggtgacaa cgtttaagtg aaaaggagtc 970 tgtgatgtgt tttcttacccttcattgtta cagtaaaaaa aaaaaaaaag ggcggccgc 1029 <210> SEQ ID NO 6 <211>LENGTH: 54 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE:6 Met Leu Leu Glu Gly Val Leu Leu Val Val Gln Ala Leu Gln Leu Ala 1 5 1015 Asn Ala Leu Asp Leu Pro Ala Gly Ser Cys Ala Phe Glu Glu Asp Thr 20 2530 Cys Gly Phe Asp Ser Val Phe Ala Phe Leu Pro Trp Ile Leu Asn Glu 35 4045 Glu Gly Lys Gly Thr Ser 50 <210> SEQ ID NO 7 <211> LENGTH: 1440 <212>TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 7 atgcagatcccgcgcgccgc tcttctcccg ctgctgctgc tgctgctggc ggcgcccgcc 60 tcggcgcagctgtcccgggc cggccgctcg gcgcctttgg ccgccgggtg cccagaccgc 120 tgcgagccggcgcgctgccc gccgcagccg gagcactgcg agggcggccg ggcccgggac 180 gcgtgcggctgctgcgaggt gtgcggcgcg cccgagggcg ccgcgtgcgg cctgcaggag 240 ggcccgtgcggcgaggggct gcagtgcgtg gtgcccttcg gggtgccagc ctcggccacg 300 gtgcggcggcgcgcgcaggc cggcctctgt gtgtgcgcca gcagcgagcc ggtgtgcggc 360 agcgacgccaacacctacgc caacctgtgc cagctgcgcg ccgccagccg ccgctccgag 420 aggctgcaccggccgccggt catcgtcctg cagcgcggag cctgcggcca agggcaggaa 480 gatcccaacagtttgcgcca taaatataac tttatcgcgg acgtggtgga gaagatcgcc 540 cctgccgtggttcatatcga attgtttcgc aagcttccgt tttctaaacg agaggtgccg 600 gtggctagtgggtctgggtt tattgtgtcg gaagatggac tgatcgtgac aaatgcccac 660 gtggtgaccaacaagcaccg ggtcaaagtt gagctgaaga acggtgccac ttacgaagcc 720 aaaatcaaggatgtggatga gaaagcagac atcgcactca tcaaaattga ccaccagggc 780 aagctgcctgtcctgctgct tggccgctcc tcagagctgc ggccgggaga gttcgtggtc 840 gccatcggaagcccgttttc ccttcaaaac acagtcacca ccgggatcgt gagcaccacc 900 cagcgaggcggcaaagagct ggggctccgc aactcagaca tggactacat ccagaccgac 960 gccatcatcaactatggaaa ctcgggaggc ccgttagtaa acctggacgg tgaagtgatt 1020 ggaattaacactttgaaagt gacagctgga atctcctttg caatcccatc tgataagatt 1080 aaaaagttcctcacggagtc ccatgaccga caggccaaag gaaaagccat caccaagaag 1140 aagtatattggtatccgaat gatgtcactc acgtccagca aagccaaaga gctgaaggac 1200 cggcaccgggacttcccaga cgtgatctca ggagcgtata taattgaagt aattcctgat 1260 accccagcagaagctggtgg tctcaaggaa aacgacgtca taatcagcat caatggacag 1320 tccgtggtctccgccaatga tgtcagcgac gtcattaaaa gggaaagcac cctgaacatg 1380 gtggtccgcaggggtaatga agatatcatg atcacagtga ttcccgaaga aattgaccca 1440 <210> SEQ IDNO 8 <211> LENGTH: 149 <212> TYPE: PRT <213> ORGANISM: Homo sapiens<400> SEQUENCE: 8 Met Val Ser Phe Arg Lys Ile Phe Ile Leu Gln Leu ValGly Leu Val 1 5 10 15 Leu Thr Tyr Asp Phe Thr Asn Cys Asp Phe Glu LysIle Lys Ala Ala 20 25 30 Tyr Leu Ser Thr Ile Ser Lys Asp Leu Ile Thr TyrMet Ser Gly Thr 35 40 45 Lys Ser Thr Glu Phe Asn Asn Thr Val Ser Cys SerAsn Arg Pro His 50 55 60 Cys Leu Thr Glu Ile Gln Ser Leu Thr Phe Asn ProThr Ala Gly Cys 65 70 75 80 Ala Ser Leu Ala Lys Glu Met Phe Ala Met LysThr Lys Ala Ala Leu 85 90 95 Ala Ile Trp Cys Pro Gly Tyr Ser Glu Thr GlnIle Asn Ala Thr Gln 100 105 110 Ala Met Lys Lys Arg Arg Lys Arg Lys ValThr Thr Asn Lys Cys Leu 115 120 125 Glu Gln Val Ser Gln Leu Gln Gly LeuTrp Arg Arg Phe Asn Arg Pro 130 135 140 Leu Leu Lys Gln Gln 145 <210>SEQ ID NO 9 <211> LENGTH: 1044 <212> TYPE: DNA <213> ORGANISM: Mouse<400> SEQUENCE: 9 atgcaggcgc gagcgctgca gctctccggg acgcccgtgc gccagctgcagaagggcgcc 60 tgcccgttgg gtctccacca gctgagcagc ccgcgctaca agttcaacttcattgctgac 120 gtggtggaga agatcgcacc agccgtggtc cacatagagc tcttcctgagacacccgctg 180 tttggccgca acgtgcccct gtccagcggt tctggcttca tcatgtcagaggccggcctg 240 atcatcacca atgcccacgt ggtgtccagc aacagtgctg ccccgggcaggcagcagctc 300 aaggtgcagc tacagaatgg ggactcctat gaggccacca tcaaagacatcgacaagaag 360 tcggacattg ccaccatcaa gatccatccc aagaaaaagc tccctgtgttgttgctgggt 420 cactcggccg acctgcggcc tggggagttt gtggtggcca tcggcagtcccttcgcccta 480 cagaacacag tgacaacggg catcgtcagc actgcccagc gggagggcagggagctgggc 540 ctccgggact ccgacatgga ctacatccag acggatgcca tcatcaactacgggaactcc 600 gggggaccac tggtgaacct ggatggcgag gtcattggca tcaacacgctcaaggtcacg 660 gctggcatct cctttgccat cccctcagac cgcatcacac ggttcctcacagagttccaa 720 gacaagcaga tcaaagactg gaagaagcgc ttcatcggca tacggatgcggacgatcaca 780 ccaagcctgg tggatgagct gaaggccagc aacccggact tcccagaggtcagcagtgga 840 atttatgtgc aagaggttgc gccgaattca ccttctcaga gaggcggcatccaagatggt 900 gacatcatcg tcaaggtcaa cgggcgtcct ctagtggact cgagtgagctgcaggaggcc 960 gtgctgaccg agtctcctct cctactggag gtgcggcggg ggaacgacgacctcctcttc 1020 agcatcgcac ctgaggtggt catg 1044 <210> SEQ ID NO 10 <211>LENGTH: 123 <212> TYPE: PRT <213> ORGANISM: Mouse <400> SEQUENCE: 10 LeuIle Pro Asp Thr Phe Leu Val Ser Phe Pro Pro Ile Pro Ile Pro 1 5 10 15Phe Pro Val Pro Phe Ile Gln Phe Leu Ile Ser Gly Gly Phe Asn Leu 20 25 30Leu Ser Leu Ser Asn Cys Ala Ala Cys Glu Gln Pro Ala Cys Leu Leu 35 40 45Lys Ile Glu Tyr Tyr Thr Leu Asn Pro Ile Pro Gly Cys Pro Ser Leu 50 55 60Pro Asp Lys Thr Phe Ala Arg Arg Thr Arg Glu Ala Leu Asn Asp His 65 70 7580 Cys Pro Gly Tyr Pro Glu Thr Glu Arg Asn Asp Gly Thr Gln Glu Met 85 9095 Ala Gln Glu Val Gln Asn Ile Cys Leu Asn Gln Thr Ser Gln Ile Leu 100105 110 Arg Leu Trp Tyr Ser Phe Met Gln Ser Pro Glu 115 120 <210> SEQ IDNO 11 <211> LENGTH: 1937 <212> TYPE: DNA <213> ORGANISM: Homo sapiens<220> FEATURE: <221> NAME/KEY: CDS <222> LOCATION: (96)...(809) <400>SEQUENCE: 11 gtcgacccac gcgtccgctt ggggatccct cagcttaaca cccacagacatcggctggtg 60 gattcccgct gcatcaaggc ctacccactg tctcc atg ctg ggc tct ccctgc 113 Met Leu Gly Ser Pro Cys 1 5 ctt ctg tgg ctc ctg gcc gtg acc ttcttg gtt ccc aga gct cag ccc 161 Leu Leu Trp Leu Leu Ala Val Thr Phe LeuVal Pro Arg Ala Gln Pro 10 15 20 ttg gcc cct caa gac ttt gaa gaa gag gaagaa gat gag act gag acg 209 Leu Ala Pro Gln Asp Phe Glu Glu Glu Glu GluAsp Glu Thr Glu Thr 25 30 35 gcg tgg ccg cct ttg ccg gct gtc ccc tgc gactac gac cac tgc cga 257 Ala Trp Pro Pro Leu Pro Ala Val Pro Cys Asp TyrAsp His Cys Arg 40 45 50 cac ctg cag gtg ccc tgt aag gag cta cag agg gccggg ccg gcg gcc 305 His Leu Gln Val Pro Cys Lys Glu Leu Gln Arg Ala GlyPro Ala Ala 55 60 65 70 tgc ctg tgc cca gga ctc tct agc cct gcc cag ccgccc gac ccg ccg 353 Cys Leu Cys Pro Gly Leu Ser Ser Pro Ala Gln Pro ProAsp Pro Pro 75 80 85 cgc atg gga gaa gtg agc att gtg gcc gaa gag ggc cgcgca gtg gtc 401 Arg Met Gly Glu Val Ser Ile Val Ala Glu Glu Gly Arg AlaVal Val 90 95 100 cac tgg tgt gcc ccc ttc tcc ccg gtc ctc cac tac tggctg ctg ctt 449 His Trp Cys Ala Pro Phe Ser Pro Val Leu His Tyr Trp LeuLeu Leu 105 110 115 tgg gac ggc agc gag gct gcg cag aag ggg ccc tcg ctgaac gct acg 497 Trp Asp Gly Ser Glu Ala Ala Gln Lys Gly Pro Ser Leu AsnAla Thr 120 125 130 gtc cgc aga gcc gaa ctg aag ggg ctg aag cca ggg ggcgtt tat gtc 545 Val Arg Arg Ala Glu Leu Lys Gly Leu Lys Pro Gly Gly ValTyr Val 135 140 145 150 gtt tgc gtg gtg gcc gct aac gag gct ggg gca agccgc gtg cct gag 593 Val Cys Val Val Ala Ala Asn Glu Ala Gly Ala Ser ArgVal Pro Glu 155 160 165 gct gga aga gag ggc ctc gag ggg gcc gac atc cctgcc ttc ggg cct 641 Ala Gly Arg Glu Gly Leu Glu Gly Ala Asp Ile Pro AlaPhe Gly Pro 170 175 180 tgc agc cgc ttt gca gtg ccg ccc aac ccc cgc actctg gtc cac gcc 689 Cys Ser Arg Phe Ala Val Pro Pro Asn Pro Arg Thr LeuVal His Ala 185 190 195 gcc gtc ggg gtg ggc acg gcc ctg gcc ctg ctg agctgt gcc gcc ctg 737 Ala Val Gly Val Gly Thr Ala Leu Ala Leu Leu Ser CysAla Ala Leu 200 205 210 gtg tgg cac ttc tgc cta cgc gat cgc tgg ggc tgcccg cgc cga gcc 785 Val Trp His Phe Cys Leu Arg Asp Arg Trp Gly Cys ProArg Arg Ala 215 220 225 230 gtc gcc cga gca gca ggg gcg ctc tgaaaggggcctgggggcat ctcgggcaca 839 Val Ala Arg Ala Ala Gly Ala Leu 235 gccagccccacctgcggcgt tcagcccggc tcctggaaag aggggaaccc gctgcctcca 899 gggagggttggacggtgagc tgggagccag ccccaggctc tagagccaca gcagagtcat 959 ggttctctgggctgagcgct tgtttaggtc cggaacttgg tgctgtttcc tggctgaggt 1019 ctgggaaagaatagaaaggg gcccccaatt tttctttttt aacggtcaga tagtaaataa 1079 tgtaacctttgcggtttaag aggataaaat ggagaatatt atgtgggtat ttatatgacc 1139 tttgtaaccatttataaagg aaaaaccaca cgacatagta atgcgaacct agagtagcag 1199 ctactccggaagctgaaatg ggaggatctc ttgagcccag gagtttgagt ccagtccagc 1259 cagggcaacacagccagacg cccttgtgtt ttgttttgtt ttgttttttg agaagaagtc 1319 tccctctgttacacagggtg gattgcaatg acacgatata tgtcggttca ctgcaacctc 1379 cacctcctaggttcaagtga ttctcccgta tcagcatcct aagtagttgg ggttacaggt 1439 gcccacgaccatgcccggct aattattgtg tttttttagt agagatgggt tttcaccatg 1499 ttggtcagcctggtctcaaa ctcctgacct caggtactcc acccaccttg gcctcccaaa 1559 gtgctgggattacaggcgtg agccacggtg cccaggcaga cccccttctt taaagatgta 1619 aaatcattcttagtccgtgg gccttacaaa tcaggtcact ggcccattgc ttgtagttag 1679 ttgatccatatcatgcaccc tcaaaacggc tctgtcaatg agtgtcttca gtgggattct 1739 gagaataaatttatattctt gctaggtaga acaaaacaaa aatgacagta atatcaagga 1799 atttctcatccctttttttc cctccatttg tatttattgc atatccactg taaaaacatt 1859 aaaggatctttaaaagaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 1919 aaaaaaaggggcggccgc 1937 <210> SEQ ID NO 12 <211> LENGTH: 238 <212> TYPE: PRT <213>ORGANISM: Homo sapiens <400> SEQUENCE: 12 Met Leu Gly Ser Pro Cys LeuLeu Trp Leu Leu Ala Val Thr Phe Leu 1 5 10 15 Val Pro Arg Ala Gln ProLeu Ala Pro Gln Asp Phe Glu Glu Glu Glu 20 25 30 Glu Asp Glu Thr Glu ThrAla Trp Pro Pro Leu Pro Ala Val Pro Cys 35 40 45 Asp Tyr Asp His Cys ArgHis Leu Gln Val Pro Cys Lys Glu Leu Gln 50 55 60 Arg Ala Gly Pro Ala AlaCys Leu Cys Pro Gly Leu Ser Ser Pro Ala 65 70 75 80 Gln Pro Pro Asp ProPro Arg Met Gly Glu Val Ser Ile Val Ala Glu 85 90 95 Glu Gly Arg Ala ValVal His Trp Cys Ala Pro Phe Ser Pro Val Leu 100 105 110 His Tyr Trp LeuLeu Leu Trp Asp Gly Ser Glu Ala Ala Gln Lys Gly 115 120 125 Pro Ser LeuAsn Ala Thr Val Arg Arg Ala Glu Leu Lys Gly Leu Lys 130 135 140 Pro GlyGly Val Tyr Val Val Cys Val Val Ala Ala Asn Glu Ala Gly 145 150 155 160Ala Ser Arg Val Pro Glu Ala Gly Arg Glu Gly Leu Glu Gly Ala Asp 165 170175 Ile Pro Ala Phe Gly Pro Cys Ser Arg Phe Ala Val Pro Pro Asn Pro 180185 190 Arg Thr Leu Val His Ala Ala Val Gly Val Gly Thr Ala Leu Ala Leu195 200 205 Leu Ser Cys Ala Ala Leu Val Trp His Phe Cys Leu Arg Asp ArgTrp 210 215 220 Gly Cys Pro Arg Arg Ala Val Ala Arg Ala Ala Gly Ala Leu225 230 235 <210> SEQ ID NO 13 <211> LENGTH: 1459 <212> TYPE: DNA <213>ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: CDS <222>LOCATION: (1)...(366) <400> SEQUENCE: 13 gtc gac cca cgc gtc cgc gag gctgcg cag aag ggg ccc ccg ctg aac 48 Val Asp Pro Arg Val Arg Glu Ala AlaGln Lys Gly Pro Pro Leu Asn 1 5 10 15 gct acg gtc cgc aga gcc gaa ctgaag ggg ctg aag cca ggg ggc att 96 Ala Thr Val Arg Arg Ala Glu Leu LysGly Leu Lys Pro Gly Gly Ile 20 25 30 tat gtc gtt tgc gta gtg gcc gct aacgag gcc ggg gca agc cgc gtg 144 Tyr Val Val Cys Val Val Ala Ala Asn GluAla Gly Ala Ser Arg Val 35 40 45 ccc cag gct gga gga gag ggc ctc gag ggggcc gac atc cct gcc ttc 192 Pro Gln Ala Gly Gly Glu Gly Leu Glu Gly AlaAsp Ile Pro Ala Phe 50 55 60 ggg cct tgc agc cgc ctt gcg gtg ccg ccc aacccc cgc act ctg gtc 240 Gly Pro Cys Ser Arg Leu Ala Val Pro Pro Asn ProArg Thr Leu Val 65 70 75 80 cac gcg gcc gtc ggg gtg ggc acg gcc ctg gccctg cta agc tgt gcc 288 His Ala Ala Val Gly Val Gly Thr Ala Leu Ala LeuLeu Ser Cys Ala 85 90 95 gcc ctg gtg tgg cac ttc tgc ctg cgc gat cgc tggggc tgc ccg cgc 336 Ala Leu Val Trp His Phe Cys Leu Arg Asp Arg Trp GlyCys Pro Arg 100 105 110 cga gcc gcc gcc cga gcc gca ggg gcg ctctgaaaggggc ctgggggcat 386 Arg Ala Ala Ala Arg Ala Ala Gly Ala Leu 115120 ctcgggcaca gacagcccca cctggggcgc tcagcctggc ccccgggaaa gaggaaaacc446 cgctgcctcc agggagggct ggacggcgag ctgggagcca gccccaggct ccagggccac506 ggcggagtca tggttctcag gactgagcgc ttgtttaggt ccggtacttg gcgctttgtt566 tcctggctga ggtctgggaa ggaatagaaa ggggccccca attttttttt aagcggccag626 ataataaata atgtaacctt tgcggtttaa gaggataaaa tggaggatat tattatgtgg686 gtatttatat gacctttgta accatttaaa aatgtaaaaa cgacctgact tagtaatgcg746 aacctatagt agcagctact ccagaggctg aaatgggagg atctcttgag cccaggagtt806 ggagtccagt ccagccaggg caacacagcc agacgccctt gttttttatt ttgttttgtt866 ttggtttttt gttttttgag gagtttccct ctgtcacaca agctggaggg caatggcgcc926 atctcagctc actgcaacgt ccacctcctg ggttcaggcg attctcctgc ctcagcatcc986 taattggtgg gtacctgtgg tcccagctac tccggaggct gaggcaggag aatggcgtgg1046 gcccgggagg cggatcttgc agtgagcgga gattgcgcca ctgcactcca gcctgggtga1106 cagagcaaga ctccctctca aaagaaaaag aaaaaagatg taaaaaccat tcttagtttg1166 tgggccttac aaatcaggcc actggcccat tgcttgtagt tagttgatcc atgtcatgca1226 ccctaaaaat ggctctgtca ctgtgagtgg cttcagtagg attttgagaa taagtttata1286 ttcttgctag gtaaaacaaa acaaaaacga cagtaatacc aaggaatctc cccccccttt1346 taccctccat ttgtgtttat tgcatatcca ctataacaac attaaaggac ctttaaaagg1406 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaggggcggc cgc 1459<210> SEQ ID NO 14 <211> LENGTH: 122 <212> TYPE: PRT <213> ORGANISM:Homo sapiens <400> SEQUENCE: 14 Val Asp Pro Arg Val Arg Glu Ala Ala GlnLys Gly Pro Pro Leu Asn 1 5 10 15 Ala Thr Val Arg Arg Ala Glu Leu LysGly Leu Lys Pro Gly Gly Ile 20 25 30 Tyr Val Val Cys Val Val Ala Ala AsnGlu Ala Gly Ala Ser Arg Val 35 40 45 Pro Gln Ala Gly Gly Glu Gly Leu GluGly Ala Asp Ile Pro Ala Phe 50 55 60 Gly Pro Cys Ser Arg Leu Ala Val ProPro Asn Pro Arg Thr Leu Val 65 70 75 80 His Ala Ala Val Gly Val Gly ThrAla Leu Ala Leu Leu Ser Cys Ala 85 90 95 Ala Leu Val Trp His Phe Cys LeuArg Asp Arg Trp Gly Cys Pro Arg 100 105 110 Arg Ala Ala Ala Arg Ala AlaGly Ala Leu 115 120 <210> SEQ ID NO 15 <211> LENGTH: 1136 <212> TYPE:DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: CDS<222> LOCATION: (110)...(823) <400> SEQUENCE: 15 gtcgacccac gcgtccggcacagcctgaga tcttggggat ccctcagcct aacacccaca 60 gacgtcagct ggtggattcccgctgcatca aggcctaccc actgtctcc atg ctg ggc 118 Met Leu Gly 1 tct ccctgc ctt ctg tgg ctc ctg gcc gtg acc ttc ttg gtt ccc aga 166 Ser Pro CysLeu Leu Trp Leu Leu Ala Val Thr Phe Leu Val Pro Arg 5 10 15 gct cag cccttg gcc cct caa gac ttt gaa gaa gag gag gca gat gag 214 Ala Gln Pro LeuAla Pro Gln Asp Phe Glu Glu Glu Glu Ala Asp Glu 20 25 30 35 act gag acggcg tgg ccg cct ttg ccg gct gtc ccc tgc gac tac gac 262 Thr Glu Thr AlaTrp Pro Pro Leu Pro Ala Val Pro Cys Asp Tyr Asp 40 45 50 cac tgc cga cacctg cag gtg ccc tgc aag gag cta cag agg gtc ggg 310 His Cys Arg His LeuGln Val Pro Cys Lys Glu Leu Gln Arg Val Gly 55 60 65 ccg gcg gcc tgc ctgtgc cca gga ctc tcc agc ccc gcc cag ccg ccc 358 Pro Ala Ala Cys Leu CysPro Gly Leu Ser Ser Pro Ala Gln Pro Pro 70 75 80 gac ccg ccg cgc atg ggagaa gtg cgc att gcg gcc gaa gag ggc cgc 406 Asp Pro Pro Arg Met Gly GluVal Arg Ile Ala Ala Glu Glu Gly Arg 85 90 95 gca gtg gtc cac tgg tgt gccccc ttc tcc ccg gtc ctc cac tac tgg 454 Ala Val Val His Trp Cys Ala ProPhe Ser Pro Val Leu His Tyr Trp 100 105 110 115 ctg ctg ctt tgg gac ggcagc gag gct gcg cag aag ggg ccc ccg ctg 502 Leu Leu Leu Trp Asp Gly SerGlu Ala Ala Gln Lys Gly Pro Pro Leu 120 125 130 aac gct acg gtc cgc agagcc gaa ctg aag ggg ctg aag cca ggg ggc 550 Asn Ala Thr Val Arg Arg AlaGlu Leu Lys Gly Leu Lys Pro Gly Gly 135 140 145 att tat gtc gtt tgc gtagtg gcc gct aac gag gcc ggg gca agc cgc 598 Ile Tyr Val Val Cys Val ValAla Ala Asn Glu Ala Gly Ala Ser Arg 150 155 160 gtg ccc cag gct gga ggagag ggc ctc gag ggg gcc gac atc cct gcc 646 Val Pro Gln Ala Gly Gly GluGly Leu Glu Gly Ala Asp Ile Pro Ala 165 170 175 ttc ggg cct tgc agc cgcctt gcg gtg ccg ccc aac ccc cgc act ctg 694 Phe Gly Pro Cys Ser Arg LeuAla Val Pro Pro Asn Pro Arg Thr Leu 180 185 190 195 gtc cac gcg gcc gtcggg gtg ggc acg gcc ctg gcc ctg cta agc tgt 742 Val His Ala Ala Val GlyVal Gly Thr Ala Leu Ala Leu Leu Ser Cys 200 205 210 gcc gcc ctg gtg tggcac ttc tgc ctg cgc gat cgc tgg ggc tgc ccg 790 Ala Ala Leu Val Trp HisPhe Cys Leu Arg Asp Arg Trp Gly Cys Pro 215 220 225 cgc cga gcc gcc gcccga gcc gca ggg gcg ctc tgaaaggggc ctgggggcat 843 Arg Arg Ala Ala AlaArg Ala Ala Gly Ala Leu 230 235 ctcgggcaca gacagcccca cctggggcgctcagcctggc ccccgggaaa gaggaaaacc 903 cgctgcctcc agggagggct ggacggcgagctgggagcca gccccaggct ccagggccac 963 ggcggagtca tggttctcag gactgagcgcttgtttaggt ccggtacttg gcgctttgtt 1023 tcctggctga ggtctgggaa ggaatagaaaggggccccca attttttttt aagcggccag 1083 ataataaata atgtaacctt tgcggtttaaaaaaaaaaaa aaagggcggc cgc 1136 <210> SEQ ID NO 16 <211> LENGTH: 238<212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 16 Met LeuGly Ser Pro Cys Leu Leu Trp Leu Leu Ala Val Thr Phe Leu 1 5 10 15 ValPro Arg Ala Gln Pro Leu Ala Pro Gln Asp Phe Glu Glu Glu Glu 20 25 30 AlaAsp Glu Thr Glu Thr Ala Trp Pro Pro Leu Pro Ala Val Pro Cys 35 40 45 AspTyr Asp His Cys Arg His Leu Gln Val Pro Cys Lys Glu Leu Gln 50 55 60 ArgVal Gly Pro Ala Ala Cys Leu Cys Pro Gly Leu Ser Ser Pro Ala 65 70 75 80Gln Pro Pro Asp Pro Pro Arg Met Gly Glu Val Arg Ile Ala Ala Glu 85 90 95Glu Gly Arg Ala Val Val His Trp Cys Ala Pro Phe Ser Pro Val Leu 100 105110 His Tyr Trp Leu Leu Leu Trp Asp Gly Ser Glu Ala Ala Gln Lys Gly 115120 125 Pro Pro Leu Asn Ala Thr Val Arg Arg Ala Glu Leu Lys Gly Leu Lys130 135 140 Pro Gly Gly Ile Tyr Val Val Cys Val Val Ala Ala Asn Glu AlaGly 145 150 155 160 Ala Ser Arg Val Pro Gln Ala Gly Gly Glu Gly Leu GluGly Ala Asp 165 170 175 Ile Pro Ala Phe Gly Pro Cys Ser Arg Leu Ala ValPro Pro Asn Pro 180 185 190 Arg Thr Leu Val His Ala Ala Val Gly Val GlyThr Ala Leu Ala Leu 195 200 205 Leu Ser Cys Ala Ala Leu Val Trp His PheCys Leu Arg Asp Arg Trp 210 215 220 Gly Cys Pro Arg Arg Ala Ala Ala ArgAla Ala Gly Ala Leu 225 230 235 <210> SEQ ID NO 17 <211> LENGTH: 2221<212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221>NAME/KEY: CDS <222> LOCATION: (79)...(795) <400> SEQUENCE: 17 cgtccgggcctctccgcctg atagccacgg atatctgggg gcaaaccctc actgtgacga 60 ggcctacccactgactcc atg ttg ggc tct ctt tcc ctt ctg tgg ctg gca 111 Met Leu Gly SerLeu Ser Leu Leu Trp Leu Ala 1 5 10 gcc atg acc acc tcc ttg gtt tcc caacct cag atc ttg acc ctg gaa 159 Ala Met Thr Thr Ser Leu Val Ser Gln ProGln Ile Leu Thr Leu Glu 15 20 25 gac tac cag gaa ggg gaa gag gat gat gtgaca gta gct aca cct tcc 207 Asp Tyr Gln Glu Gly Glu Glu Asp Asp Val ThrVal Ala Thr Pro Ser 30 35 40 tta gct gtc cgt tgc gac tat gac cgt tgc cgccac ctg cag gtg tcc 255 Leu Ala Val Arg Cys Asp Tyr Asp Arg Cys Arg HisLeu Gln Val Ser 45 50 55 tgc cag gag ctg cag aag gtt ggg cca gta gcc tgcctg tgc cca ggg 303 Cys Gln Glu Leu Gln Lys Val Gly Pro Val Ala Cys LeuCys Pro Gly 60 65 70 75 ctc tcc agg gaa gat caa cag cca gag cct cct cgcctg gga gaa gtg 351 Leu Ser Arg Glu Asp Gln Gln Pro Glu Pro Pro Arg LeuGly Glu Val 80 85 90 caa ata atg gct gaa gaa ggc tac gca gtg gtt cac tggtgt gct ccc 399 Gln Ile Met Ala Glu Glu Gly Tyr Ala Val Val His Trp CysAla Pro 95 100 105 ttc tct cca gtc agc cac tac tgg ctt ctg ctt tgg gaaagc aac ggg 447 Phe Ser Pro Val Ser His Tyr Trp Leu Leu Leu Trp Glu SerAsn Gly 110 115 120 gct cca cag aag agt gcc cct ctc aat gct aca gtt cgaaga gca gag 495 Ala Pro Gln Lys Ser Ala Pro Leu Asn Ala Thr Val Arg ArgAla Glu 125 130 135 ctg aag gga cta aag cct ggg gtt gct tat gtc ctt tgcgtg gtg gct 543 Leu Lys Gly Leu Lys Pro Gly Val Ala Tyr Val Leu Cys ValVal Ala 140 145 150 155 gct aat gac gca ggt gag agc aat gtt cct ggg gcagaa gtc gag ggt 591 Ala Asn Asp Ala Gly Glu Ser Asn Val Pro Gly Ala GluVal Glu Gly 160 165 170 cct gag aac tgg act ggc cct tcc ttt ggg ccc tgtcgc aag ttt atc 639 Pro Glu Asn Trp Thr Gly Pro Ser Phe Gly Pro Cys ArgLys Phe Ile 175 180 185 atg ccg cct aag cct gtt acc ctg gtc tat gca gccgtg gga gtg ggc 687 Met Pro Pro Lys Pro Val Thr Leu Val Tyr Ala Ala ValGly Val Gly 190 195 200 aca gcc tta gct ctg ctg agc tgt gca gcc ctg gtttgg cat ttc tgc 735 Thr Ala Leu Ala Leu Leu Ser Cys Ala Ala Leu Val TrpHis Phe Cys 205 210 215 ctt cgt gag cga tgg ggt tgc ccc cga cgt caa ggtatg gcc caa gcg 783 Leu Arg Glu Arg Trp Gly Cys Pro Arg Arg Gln Gly MetAla Gln Ala 220 225 230 235 tca gaa gct ctc tgacaggagt cccctcgactacaaacaact catctggaga 835 Ser Glu Ala Leu gcccaaccca ctcccaggaggagtgtgggg cttgttgcca cctggcaacc agaggcacag 895 ccaagccaga gcggaagcccaggcaattag cctcagcact gagggcttgg ttagtcccta 955 actggtcact atgttccttccctgttgggg gttagaaaaa gtagcaatta ttccttggag 1015 gtctgatgaa aatgatttaagctttatggg tttgaagggg taaaattaca gacattatac 1075 atgaacttat atatagccagttaaaatgga gctatttaaa ggcctggcat ggtggtttac 1135 aattttggtc tccagcgccctggaggcaga ggcaggcgga tctgagtttc cggggcagcc 1195 tgatctacat agaaagattccaggccaacc cagataatat agtgagaccc tgtctcaaaa 1255 agagtaaaac agaagcaaaacaaacaaaag gtggggcggg atagagagat tgttcagcag 1315 ttaagaatac tggctatttttccagaggac agaattttat tcctagcatc cacatggcag 1375 ctcacaacca tctgtaattccatttccagg agatccagtg tctaattctg acctctgcca 1435 gcatcaggca catacatacgcacacataca tacatacata catacataca cacacacaca 1495 cacacacaca cacacacagagagagacaaa acactcatac acataaaata aaaattaatt 1555 tgaagtgtag ctgtttaaaaatgtaaactg ttcatagctc ataggtctct cacagcaagc 1615 agcagactac atttggcctgttggctgatt tgccaacacc tatcattctc aaagggactt 1675 tgtgactgtc ggtggcttccctgcatattt tgagaataag ctgagttttg ccaacacctg 1735 ttattctgaa aaggactctgcgactgtggg tggcttccac gcatgttttg agaataagca 1795 gggtagatgt ggagactggagctctgtctt tctgctactt gttgtttcct tcctaaggat 1855 gatcctgctc agactccacctggggctatg gaagctgggg attaaaaatc agcatgggct 1915 ggaggagaca gggcccaagcttctggctac ataagttagt ggtcttgttt gttttggggg 1975 tttttgtttg tttgttttttcaagacaggg tttctctgtg tagctctggc tgtcctggaa 2035 ctcactttgt agaccaggctggcctcgaac tcagaaatcc gcctgcctct gcctcccaag 2095 tgctgggatt aaaggcatgcgccaccaccg cccagcagtg gttttatttg taactaacag 2155 tttataccaa tgactccccacaactttgtg taattgtttt tccactgtat taacattaaa 2215 gggaat 2221 <210> SEQID NO 18 <211> LENGTH: 239 <212> TYPE: PRT <213> ORGANISM: Homo sapiens<400> SEQUENCE: 18 Met Leu Gly Ser Leu Ser Leu Leu Trp Leu Ala Ala MetThr Thr Ser 1 5 10 15 Leu Val Ser Gln Pro Gln Ile Leu Thr Leu Glu AspTyr Gln Glu Gly 20 25 30 Glu Glu Asp Asp Val Thr Val Ala Thr Pro Ser LeuAla Val Arg Cys 35 40 45 Asp Tyr Asp Arg Cys Arg His Leu Gln Val Ser CysGln Glu Leu Gln 50 55 60 Lys Val Gly Pro Val Ala Cys Leu Cys Pro Gly LeuSer Arg Glu Asp 65 70 75 80 Gln Gln Pro Glu Pro Pro Arg Leu Gly Glu ValGln Ile Met Ala Glu 85 90 95 Glu Gly Tyr Ala Val Val His Trp Cys Ala ProPhe Ser Pro Val Ser 100 105 110 His Tyr Trp Leu Leu Leu Trp Glu Ser AsnGly Ala Pro Gln Lys Ser 115 120 125 Ala Pro Leu Asn Ala Thr Val Arg ArgAla Glu Leu Lys Gly Leu Lys 130 135 140 Pro Gly Val Ala Tyr Val Leu CysVal Val Ala Ala Asn Asp Ala Gly 145 150 155 160 Glu Ser Asn Val Pro GlyAla Glu Val Glu Gly Pro Glu Asn Trp Thr 165 170 175 Gly Pro Ser Phe GlyPro Cys Arg Lys Phe Ile Met Pro Pro Lys Pro 180 185 190 Val Thr Leu ValTyr Ala Ala Val Gly Val Gly Thr Ala Leu Ala Leu 195 200 205 Leu Ser CysAla Ala Leu Val Trp His Phe Cys Leu Arg Glu Arg Trp 210 215 220 Gly CysPro Arg Arg Gln Gly Met Ala Gln Ala Ser Glu Ala Leu 225 230 235 <210>SEQ ID NO 19 <211> LENGTH: 1801 <212> TYPE: DNA <213> ORGANISM: Homosapiens <400> SEQUENCE: 19 gtcgacccac gcgtccggcg gaggttgtgg ctgcaccgtggtcctgggct tggtcctggg 60 cttgatgcgt ctgtttgtcc gtccgtccgt ccgtcccgccatggctgcgc cggcgccctc 120 tccgtggacc ctttcgctgc tgctgttgtt gctactgccgtctccgggtg cccatggcga 180 gctgtgcagg cccttcggtg aagacaattc gatcccagagtcctgtcctg acttctgttg 240 tggctcctgt tccagccaat actgctgctc tgacgtgctgaagaaaatcc agtggaatga 300 ggaaatgtgc cctgagccag agtccagcag attttccgcccacccggaga caccagaaca 360 gctgggttca gcgctgaagt atcagtccag tcttgacagtgacaacatgc cagggttcgg 420 agcgaccgtg gccatcggcc tgaccgtctt cgtggtgtttatcgctacca tcattgtgtg 480 ctttacctgc tcctgctgct gtctatataa gatgtgctgccgcccacgac ctgtcgtgtc 540 caacaccaca actactaccg tggttcacac cgcttaccctcagcctcaac ctgtggcccc 600 cagctatcct ggaccaacat accagggcta ccatcccatgcccccccagc caggaatgcc 660 agcagcaccc tacccaacgc agtaccctcc accctacctggcccagccca cagggccacc 720 agcctatcat gagacgttgg ctggagccag ccagcctccatacaacccgg cctacatgga 780 tcccccaaag gcagttccct gagcctgccc ccagcctctttggctaacat ttgattatgt 840 catgtgtgtg tgagtgctat gcagagttct ttactgctgtctgtggtgcg tgtgccttgt 900 ctagacatgt ggcttcctct gctgatgacc aggtaggcacaaatcttacc agtgctggtt 960 gggaccaatc tgttttcttc ctcacttgaa attgtaatttctgaaatttc aagtaaatta 1020 aaaacaatag ggtaggaggt atttcccgct tcaccccaaggtgaccagcc atagcctgcc 1080 acacatagga gagcaagctt tttgtgggtc catgtcctgctttggggagt agccagctag 1140 ctgctgctat gggtttattc ccagggcttg gctgcatttagctggacaga gaacaagggg 1200 cctcagtggc agtgggtcag tgactgatgt cagagcacactaggcagaga gccccgtccg 1260 tctccatcag ctgtctgtct ggacggtccc actgtctttcctgggactat gtagagggcc 1320 acatgtattc actattcagg ctccagtggc ttccaggccaggggcctctg tctactacac 1380 actctggttt ctccctacag tgtcttttta cgattagccaaacatattgc ctgttttttg 1440 tatccagatg tgtgataatt ggtgaggttg aaatccttggttcctggaga acaggaaacc 1500 tgacctctga cagtccgttt cccttgacac cagcttcatagaatacctga ctcctgtact 1560 acagtccagt ttgttccagt agcagggaca ccagggccaggggttatctg gaccaagggt 1620 gggggtggag agcctggatg gtagctctgg accagatgtgaatgcctcca tattccctgt 1680 tggttcctgt ttcactggct gttttagttt tgtgttaattggtgtttctg agcattcaaa 1740 ctccgcaccc tcgtttataa taaatgaata tttggaaaaaaaaaaaaaaa aaaaaaaaaa 1800 a 1801 <210> SEQ ID NO 20 <211> LENGTH: 245<212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 20 Met ArgLeu Phe Val Arg Pro Ser Val Arg Pro Ala Met Ala Ala Pro 1 5 10 15 AlaPro Ser Pro Trp Thr Leu Ser Leu Leu Leu Leu Leu Leu Leu Pro 20 25 30 SerPro Gly Ala His Gly Glu Leu Cys Arg Pro Phe Gly Glu Asp Asn 35 40 45 SerIle Pro Glu Ser Cys Pro Asp Phe Cys Cys Gly Ser Cys Ser Ser 50 55 60 GlnTyr Cys Cys Ser Asp Val Leu Lys Lys Ile Gln Trp Asn Glu Glu 65 70 75 80Met Cys Pro Glu Pro Glu Ser Ser Arg Phe Ser Ala His Pro Glu Thr 85 90 95Pro Glu Gln Leu Gly Ser Ala Leu Lys Tyr Gln Ser Ser Leu Asp Ser 100 105110 Asp Asn Met Pro Gly Phe Gly Ala Thr Val Ala Ile Gly Leu Thr Val 115120 125 Phe Val Val Phe Ile Ala Thr Ile Ile Val Cys Phe Thr Cys Ser Cys130 135 140 Cys Cys Leu Tyr Lys Met Cys Cys Arg Pro Arg Pro Val Val SerAsn 145 150 155 160 Thr Thr Thr Thr Thr Val Val His Thr Ala Tyr Pro GlnPro Gln Pro 165 170 175 Val Ala Pro Ser Tyr Pro Gly Pro Thr Tyr Gln GlyTyr His Pro Met 180 185 190 Pro Pro Gln Pro Gly Met Pro Ala Ala Pro TyrPro Thr Gln Tyr Pro 195 200 205 Pro Pro Tyr Leu Ala Gln Pro Thr Gly ProPro Ala Tyr His Glu Thr 210 215 220 Leu Ala Gly Ala Ser Gln Pro Pro TyrAsn Pro Ala Tyr Met Asp Pro 225 230 235 240 Pro Lys Ala Val Pro 245<210> SEQ ID NO 21 <211> LENGTH: 1858 <212> TYPE: DNA <213> ORGANISM:Mus musculus <400> SEQUENCE: 21 gtcgacccac gcgtccgcgc ggaggttgcggcggcaccgt ggtcttgggc ttggtccgtc 60 tgttcgtccg tccgttggtc tgtcccgccatggctgcgcc ggcgccctct ctgtggaccc 120 tattgctgct gctgttgctg ctgccgccgcctccgggtgc ccatggtgag ctgtgcaggc 180 cctttggtga agacaattcg atcccagtgttctgtcctga tttctgttgt ggttcctgtt 240 ccaaccaata ctgctgctcg gacgtgctgaggaaaatcca gtggaatgag gaaatgtgtc 300 ctgagccaga gtccagcaga ttttccacccccgcggagga gacacccgaa catctgggtt 360 cagcgctgaa atttcgatcc agttttgacagtgaccctat gtcagggttc ggagcgaccg 420 tcgccattgg cgtgaccatc tttgtggtgtttattgccac tatcatcatc tgcttcacct 480 gctcctgctg ctgtctgtat aagatgtgctgcccccaacg ccctgtcgtg accaacacca 540 caactactac cgtggttcat gccccttaccctcagcctca acctcaacct gtggccccca 600 gctatcctgg accaacatac cagggctaccatcccatgcc ccccccagcc aggaatgcca 660 gcagcaccct acccaacgca gtacccaccaccctacctgg cccagcccac agggccgcca 720 ccctaccatg agtccttggc tggagccagccagcctccat acaacccgac ctacatggat 780 tccctaaaga caattccctg aacctgcccccagcctcttt ggctgccatt tatgtcgtgt 840 gtgagtgagt gatacgcaga gttctttactgctgtctgtg gtgtgtgtgc cttgtctaga 900 catgtggctt cctctgctgt tgaccaggtaggcgcaagtc ttaccagtgt gggtcgggac 960 caacctgttt tcttcctcac ttgaaattgtactttctgaa atttcaagca aattaaaaac 1020 aataaggtag gaggtatttc ccacgtcaccccaaggtgac cagccatggc ctgtcatact 1080 taggagagca agctttttgc gggtacagagcaggctttgg ggggtaacca gctagctgct 1140 gctaggcctt tattcccagg gtttggctgcattggcagtg aggcaggtgg ctgggggtga 1200 caccaggtga caaggggact cagtggcagggggtcacacc aggcagaaca ccatacactc 1260 tccatcagct gtctgtctgg atgtcactgtccttcccggg gctgtataga gggccacatg 1320 tgttcactat tcaggctcca ctgggggaattttcctacct ttgctggctt ggctcctgct 1380 cccaggccag ggacctcggt ctgtctactacacactctgg tttctccctg cactgtcttt 1440 ttactgttag ccaaacattt tgcctgttttctgtctccag atgtgtgata attggtgtga 1500 ggttgaaatc cctggttcct ggaggacagacaacctgacc tccgactgtc agtttccctt 1560 gacaccatct tcatagaaat acctgactcctgtaccacag tccagtttgt cccagtagca 1620 gggacaccaa ggccaatggg ttatctggaccaaaggtggg gtggagggcc tagatggtat 1680 ctccggccca gatgtgaata cctccatattccctgttggt tcctgtttca ctggctgttt 1740 tagctttgtg ttgattggtg tttctgagcattcagactcc gcaccctcat ttctaataaa 1800 tgcaacattg gaaaaaaaaa aaaaaaaaaaaaaaaaaaaa aaaaaaaagg gcggccgc 1858 <210> SEQ ID NO 22 <211> LENGTH: 213<212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 22 Met AlaAla Pro Ala Pro Ser Leu Trp Thr Leu Leu Leu Leu Leu Leu 1 5 10 15 LeuLeu Pro Pro Pro Pro Gly Ala His Gly Glu Leu Cys Arg Pro Phe 20 25 30 GlyGlu Asp Asn Ser Ile Pro Val Phe Cys Pro Asp Phe Cys Cys Gly 35 40 45 SerCys Ser Asn Gln Tyr Cys Cys Ser Asp Val Leu Arg Lys Ile Gln 50 55 60 TrpAsn Glu Glu Met Cys Pro Glu Pro Glu Ser Ser Arg Phe Ser Thr 65 70 75 80Pro Ala Glu Glu Thr Pro Glu His Leu Gly Ser Ala Leu Lys Phe Arg 85 90 95Ser Ser Phe Asp Ser Asp Pro Met Ser Gly Phe Gly Ala Thr Val Ala 100 105110 Ile Gly Val Thr Ile Phe Val Val Phe Ile Ala Thr Ile Ile Ile Cys 115120 125 Phe Thr Cys Ser Cys Cys Cys Leu Tyr Lys Met Cys Cys Pro Gln Arg130 135 140 Pro Val Val Thr Asn Thr Thr Thr Thr Thr Val Val His Ala ProTyr 145 150 155 160 Pro Gln Pro Gln Pro Gln Pro Val Ala Pro Ser Tyr ProGly Pro Thr 165 170 175 Tyr Gln Gly Tyr His Pro Met Pro Pro Pro Ala ArgAsn Ala Ser Ser 180 185 190 Thr Leu Pro Asn Ala Val Pro Thr Thr Leu ProGly Pro Ala His Arg 195 200 205 Ala Ala Thr Leu Pro 210 <210> SEQ ID NO23 <211> LENGTH: 1948 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220>FEATURE: <221> NAME/KEY: CDS <222> LOCATION: (314)...(1432) <221>NAME/KEY: misc_feature <222> LOCATION: (1)...(1948) <223> OTHERINFORMATION: n = A,T,C or G <400> SEQUENCE: 23 cgcttactcc tttgccttcgcaaacaggga aaagtgttcc acgaagcggt agcgcctttc 60 cgcctcgcgt tttcctccctgaccctggtc ccggctcccg tccgggcgcc agctggtggg 120 gcgagcgccg ggagcccatctgcccccagg ggcacggggc gcggggccgg ctcccgcccg 180 gcacatggct gcagccacctcgcgcgcacc ccgaggcgcc gcgcccagct cgcccgaggt 240 ccgtcggagg cgcccggccgccccggagcc aagcagcaac tgagcgggga agcgcccgcg 300 tccggggatc ggg atg tccctc ctc ctt ctc ctc ttg cta gtt tcc tac 349 Met Ser Leu Leu Leu Leu LeuLeu Leu Val Ser Tyr 1 5 10 tat gtt gga acc ttg ggg act cac act gag atcaag aga gtg gca gag 397 Tyr Val Gly Thr Leu Gly Thr His Thr Glu Ile LysArg Val Ala Glu 15 20 25 gaa aag gtc act ttg ccc tgc cac cat caa ctg gggctt cca gaa aaa 445 Glu Lys Val Thr Leu Pro Cys His His Gln Leu Gly LeuPro Glu Lys 30 35 40 gac act ctg gat att gaa tgg ctg ctc acc gat aat gaaggg aac caa 493 Asp Thr Leu Asp Ile Glu Trp Leu Leu Thr Asp Asn Glu GlyAsn Gln 45 50 55 60 aaa gtg gtg atc act tac tcc agt cgt cat gtc tac aataac ttg act 541 Lys Val Val Ile Thr Tyr Ser Ser Arg His Val Tyr Asn AsnLeu Thr 65 70 75 gag gaa cag aag ggc cga gtg gcc ttt gct tcc aat ttc ctggca gga 589 Glu Glu Gln Lys Gly Arg Val Ala Phe Ala Ser Asn Phe Leu AlaGly 80 85 90 gat gcc tcc ttg cag att gaa cct ctg aag ccc agt gat gag ggccgg 637 Asp Ala Ser Leu Gln Ile Glu Pro Leu Lys Pro Ser Asp Glu Gly Arg95 100 105 tac acc tgt aag gtt aag aat tca ggg cgc tac gtg tgg agc catgtc 685 Tyr Thr Cys Lys Val Lys Asn Ser Gly Arg Tyr Val Trp Ser His Val110 115 120 atc tta aaa gtc tta gtg aga cca tcc aag ccc aag tgt gag ttggaa 733 Ile Leu Lys Val Leu Val Arg Pro Ser Lys Pro Lys Cys Glu Leu Glu125 130 135 140 gga gag ctg aca gaa gga agt gac ctg act ttg cag tgt gagtca tcc 781 Gly Glu Leu Thr Glu Gly Ser Asp Leu Thr Leu Gln Cys Glu SerSer 145 150 155 tct ggc aca gag ccc att gtg tat tac tgg cag cga atc cgagag aaa 829 Ser Gly Thr Glu Pro Ile Val Tyr Tyr Trp Gln Arg Ile Arg GluLys 160 165 170 gag gga gag gat gaa cgt ctg cct ccc aaa tct agg att gactac aac 877 Glu Gly Glu Asp Glu Arg Leu Pro Pro Lys Ser Arg Ile Asp TyrAsn 175 180 185 cac cct gga cga gtt ctg ctg cag aat ctt acc atg tcc tactct gga 925 His Pro Gly Arg Val Leu Leu Gln Asn Leu Thr Met Ser Tyr SerGly 190 195 200 ctg tac cag tgc aca gca ggc aac gaa gct ggg aag gaa agctgt gtg 973 Leu Tyr Gln Cys Thr Ala Gly Asn Glu Ala Gly Lys Glu Ser CysVal 205 210 215 220 gtg cga gta act gta cag tat gta caa agc atc ggc atggtt gca gga 1021 Val Arg Val Thr Val Gln Tyr Val Gln Ser Ile Gly Met ValAla Gly 225 230 235 gca gtg aca ggc ata gtg gct gga gcc ctg ctg att ttcctc ttg gtg 1069 Ala Val Thr Gly Ile Val Ala Gly Ala Leu Leu Ile Phe LeuLeu Val 240 245 250 tgg ctg cta atc cga agg aaa gac aaa gaa aga tat gaggaa gaa gag 1117 Trp Leu Leu Ile Arg Arg Lys Asp Lys Glu Arg Tyr Glu GluGlu Glu 255 260 265 aga cct aat gaa att cga gaa gat gct gaa gct cca aaagcc cgt ctt 1165 Arg Pro Asn Glu Ile Arg Glu Asp Ala Glu Ala Pro Lys AlaArg Leu 270 275 280 gtg aaa ccc agc tcc tct tcc tca ggc tct cgg agc tcacgc tct ggt 1213 Val Lys Pro Ser Ser Ser Ser Ser Gly Ser Arg Ser Ser ArgSer Gly 285 290 295 300 tct tcc tcc act cgc tcc aca gca aat agt gcc tcacgc agc cag cgg 1261 Ser Ser Ser Thr Arg Ser Thr Ala Asn Ser Ala Ser ArgSer Gln Arg 305 310 315 aca ctg tca act gac gca gca ccc cag cca ggg ctggcc acc cag gca 1309 Thr Leu Ser Thr Asp Ala Ala Pro Gln Pro Gly Leu AlaThr Gln Ala 320 325 330 tac agc cta gtg ggg cca gag gtg aga ggt tct gaacca aag aaa gtc 1357 Tyr Ser Leu Val Gly Pro Glu Val Arg Gly Ser Glu ProLys Lys Val 335 340 345 cac cat gct aat ctg acc aaa gca gaa acc aca cccagc atg atc ccc 1405 His His Ala Asn Leu Thr Lys Ala Glu Thr Thr Pro SerMet Ile Pro 350 355 360 agc cag agc aga gcc ttc caa acg gtc tgaattacaatggacttgac 1452 Ser Gln Ser Arg Ala Phe Gln Thr Val 365 370 tcccacgctttcctaggagt cagggtcttt ggactcttct cgtcattgga gctcaagtca 1512 ccagccacacaaccagatga gaggtcatct aagtagcagt gagcattgca cggaacagat 1572 tcagatgagcattttcctta tacaatacca aacaagcaaa aggatgtaag ctgattcatc 1632 tgtaaaaaggcatcttattg tgcctttaga ccagagtaag ggaaagcagg agtccaaatc 1692 tatttgttgaccaggacctg tggtgaagaa aggttgggga aaggtgaggt gaatatacct 1752 aaaacttttaatgtgggata ttttgtatca gtgctttgat tcacaatttt caagaggaaa 1812 tgggatgctgtttgtaaatt ttctatgcat ttctgcaaac ttattggatt attagttatt 1872 cagacagtcaagcagaaccc ncagccttat tacncctgtc tacaccatgt actgagctaa 1932 ccacttttaagaaact 1948 <210> SEQ ID NO 24 <211> LENGTH: 373 <212> TYPE: PRT <213>ORGANISM: Homo sapiens <400> SEQUENCE: 24 Met Ser Leu Leu Leu Leu LeuLeu Leu Val Ser Tyr Tyr Val Gly Thr 1 5 10 15 Leu Gly Thr His Thr GluIle Lys Arg Val Ala Glu Glu Lys Val Thr 20 25 30 Leu Pro Cys His His GlnLeu Gly Leu Pro Glu Lys Asp Thr Leu Asp 35 40 45 Ile Glu Trp Leu Leu ThrAsp Asn Glu Gly Asn Gln Lys Val Val Ile 50 55 60 Thr Tyr Ser Ser Arg HisVal Tyr Asn Asn Leu Thr Glu Glu Gln Lys 65 70 75 80 Gly Arg Val Ala PheAla Ser Asn Phe Leu Ala Gly Asp Ala Ser Leu 85 90 95 Gln Ile Glu Pro LeuLys Pro Ser Asp Glu Gly Arg Tyr Thr Cys Lys 100 105 110 Val Lys Asn SerGly Arg Tyr Val Trp Ser His Val Ile Leu Lys Val 115 120 125 Leu Val ArgPro Ser Lys Pro Lys Cys Glu Leu Glu Gly Glu Leu Thr 130 135 140 Glu GlySer Asp Leu Thr Leu Gln Cys Glu Ser Ser Ser Gly Thr Glu 145 150 155 160Pro Ile Val Tyr Tyr Trp Gln Arg Ile Arg Glu Lys Glu Gly Glu Asp 165 170175 Glu Arg Leu Pro Pro Lys Ser Arg Ile Asp Tyr Asn His Pro Gly Arg 180185 190 Val Leu Leu Gln Asn Leu Thr Met Ser Tyr Ser Gly Leu Tyr Gln Cys195 200 205 Thr Ala Gly Asn Glu Ala Gly Lys Glu Ser Cys Val Val Arg ValThr 210 215 220 Val Gln Tyr Val Gln Ser Ile Gly Met Val Ala Gly Ala ValThr Gly 225 230 235 240 Ile Val Ala Gly Ala Leu Leu Ile Phe Leu Leu ValTrp Leu Leu Ile 245 250 255 Arg Arg Lys Asp Lys Glu Arg Tyr Glu Glu GluGlu Arg Pro Asn Glu 260 265 270 Ile Arg Glu Asp Ala Glu Ala Pro Lys AlaArg Leu Val Lys Pro Ser 275 280 285 Ser Ser Ser Ser Gly Ser Arg Ser SerArg Ser Gly Ser Ser Ser Thr 290 295 300 Arg Ser Thr Ala Asn Ser Ala SerArg Ser Gln Arg Thr Leu Ser Thr 305 310 315 320 Asp Ala Ala Pro Gln ProGly Leu Ala Thr Gln Ala Tyr Ser Leu Val 325 330 335 Gly Pro Glu Val ArgGly Ser Glu Pro Lys Lys Val His His Ala Asn 340 345 350 Leu Thr Lys AlaGlu Thr Thr Pro Ser Met Ile Pro Ser Gln Ser Arg 355 360 365 Ala Phe GlnThr Val 370 <210> SEQ ID NO 25 <211> LENGTH: 1949 <212> TYPE: DNA <213>ORGANISM: Mus musculus <220> FEATURE: <221> NAME/KEY: CDS <222>LOCATION: (304)...(1422) <400> SEQUENCE: 25 gtcgacccac gcgtccggttccacgaagcg gtagctcctt gccgcctcgc cttctcctcc 60 ctaaccctgg gcccggcccccgtcccggcg cgagctggtg gagccagggc tagaagccct 120 cggtgccccc ggagcgcagcgcgcagggga cccgggcgcg gggccagcgc ccgcacatgg 180 ctgcagcccc ccgcgcgcaccccgaggcgc cgcgccctgc tcacagaagg tccgtcggct 240 gggctcggtc gccctgcagccaggctgcgc tgagccggga agtgcccgtg tccggagatc 300 ggg atg tcc ctc ttc ttcctc tgg cta gta tcc tat tat gtt gga acg 348 Met Ser Leu Phe Phe Leu TrpLeu Val Ser Tyr Tyr Val Gly Thr 1 5 10 15 ctg gga act cac act gag atcaag aga gtg gca gag gaa aag gtt acc 396 Leu Gly Thr His Thr Glu Ile LysArg Val Ala Glu Glu Lys Val Thr 20 25 30 ttg ccc tgt cac cat caa ctg gggctt ccc gag aaa gac acc ctg gac 444 Leu Pro Cys His His Gln Leu Gly LeuPro Glu Lys Asp Thr Leu Asp 35 40 45 att gaa tgg ctg ctc acc gat aat gaaggg aac caa aaa gtg gtt att 492 Ile Glu Trp Leu Leu Thr Asp Asn Glu GlyAsn Gln Lys Val Val Ile 50 55 60 acg tat tcc agc cgt cat gtc tac aat aacttg acc gag gag cag aag 540 Thr Tyr Ser Ser Arg His Val Tyr Asn Asn LeuThr Glu Glu Gln Lys 65 70 75 ggc cga gtg gcc ttc gct tcc aac ttc ctg gcagga gat gct tcc ctg 588 Gly Arg Val Ala Phe Ala Ser Asn Phe Leu Ala GlyAsp Ala Ser Leu 80 85 90 95 cag att gag cct ctg aaa ccc agt gat gaa ggcaga tac acc tgc aag 636 Gln Ile Glu Pro Leu Lys Pro Ser Asp Glu Gly ArgTyr Thr Cys Lys 100 105 110 gtg aag aat tca gga cgc tat gtc tgg agc catgtc atc ttg aaa gtg 684 Val Lys Asn Ser Gly Arg Tyr Val Trp Ser His ValIle Leu Lys Val 115 120 125 cta gtg aga cca tcc aag ccc aag tgt gag ctggaa gga gag ccg acc 732 Leu Val Arg Pro Ser Lys Pro Lys Cys Glu Leu GluGly Glu Pro Thr 130 135 140 gaa gga agt gac ctg acg ctg cag tgt gag tctgcc tct gga act aag 780 Glu Gly Ser Asp Leu Thr Leu Gln Cys Glu Ser AlaSer Gly Thr Lys 145 150 155 ccc att gtg tat tat tgg cag cga atc cgg gagaag gag gga gaa gat 828 Pro Ile Val Tyr Tyr Trp Gln Arg Ile Arg Glu LysGlu Gly Glu Asp 160 165 170 175 gaa cac ctg cca ccc aaa tcc aga att gattac aac aac cct ggc cga 876 Glu His Leu Pro Pro Lys Ser Arg Ile Asp TyrAsn Asn Pro Gly Arg 180 185 190 gtg ctg ctg cag aat ctc acc atg gcc tcctct ggg ctt tac cag tgc 924 Val Leu Leu Gln Asn Leu Thr Met Ala Ser SerGly Leu Tyr Gln Cys 195 200 205 aca gca ggc aac gag gct gga aag gag agctgt gtg gta cgg gtg act 972 Thr Ala Gly Asn Glu Ala Gly Lys Glu Ser CysVal Val Arg Val Thr 210 215 220 gta cag tat gtg cag agc att ggc atg gtggca gga gca gtg aca ggc 1020 Val Gln Tyr Val Gln Ser Ile Gly Met Val AlaGly Ala Val Thr Gly 225 230 235 ata gtg gca gga gcc ctg ctc att ttc ctcctg ata tgg ctg cta ata 1068 Ile Val Ala Gly Ala Leu Leu Ile Phe Leu LeuIle Trp Leu Leu Ile 240 245 250 255 cga agg aaa agc aaa gac aga tac gaggaa gaa gac aga cct aat gaa 1116 Arg Arg Lys Ser Lys Asp Arg Tyr Glu GluGlu Asp Arg Pro Asn Glu 260 265 270 atc cga gaa gac gcc gaa gcg ccc cgagcc cgc ctt gtg aag cct agc 1164 Ile Arg Glu Asp Ala Glu Ala Pro Arg AlaArg Leu Val Lys Pro Ser 275 280 285 tcc tct tcc tca ggc tcc cgg agc tcacgc tct ggc tcc tcc tcc acc 1212 Ser Ser Ser Ser Gly Ser Arg Ser Ser ArgSer Gly Ser Ser Ser Thr 290 295 300 cgc tcc acc ggg aac agt gcc tcc agaagc cag cgg acg ctg tcg agt 1260 Arg Ser Thr Gly Asn Ser Ala Ser Arg SerGln Arg Thr Leu Ser Ser 305 310 315 gaa gca gcg ccg cag cag ccc ggg ctagcc ccg cag gca tac agc ctc 1308 Glu Ala Ala Pro Gln Gln Pro Gly Leu AlaPro Gln Ala Tyr Ser Leu 320 325 330 335 ata gga ccg gaa gtg aga ggt tctgaa cca aag aaa gtc cac cat acg 1356 Ile Gly Pro Glu Val Arg Gly Ser GluPro Lys Lys Val His His Thr 340 345 350 acc ctg acc aaa gca gaa acc acactc agc aca acg ccc agc cag agc 1404 Thr Leu Thr Lys Ala Glu Thr Thr LeuSer Thr Thr Pro Ser Gln Ser 355 360 365 aaa gcc ttc caa act gtctgacttagag tggacttgac ttgcgcttgc 1452 Lys Ala Phe Gln Thr Val 370cccaaagtca ggatcttagc ctagtcactg gagctcgtcc accagccacg caagcccctc 1512agccagatac gatctcactt aagtagctgc agaaatggca cggaccagtt ctgatgagta 1572ccctccttat ataggatacc aaacaaacac aaggacggag gctgaccatc tatctctaaa 1632ggcacctcac tgtgccttca gacagagtgg aggggaggag gggcccaagc ttatttggtg 1692aaaataaagg gaaaggtgag gctgcacaca cctgaaacat cttacctagg atgttgcaag 1752tcaccacagt caagaagaag cgggaatctc gtagatcaat tttctattca tttctgcaaa 1812tttattggat tagtgtgatt attcagatag tcaaaacaga agcccacgcc ttataatata 1872cctatctgca acatgtactg ggagaactgc gtttaagaaa ttcacattaa aaaaaaaaaa 1932aaaaaaaggg cggccgc 1949 <210> SEQ ID NO 26 <211> LENGTH: 373 <212> TYPE:PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 26 Met Ser Leu Phe PheLeu Trp Leu Val Ser Tyr Tyr Val Gly Thr Leu 1 5 10 15 Gly Thr His ThrGlu Ile Lys Arg Val Ala Glu Glu Lys Val Thr Leu 20 25 30 Pro Cys His HisGln Leu Gly Leu Pro Glu Lys Asp Thr Leu Asp Ile 35 40 45 Glu Trp Leu LeuThr Asp Asn Glu Gly Asn Gln Lys Val Val Ile Thr 50 55 60 Tyr Ser Ser ArgHis Val Tyr Asn Asn Leu Thr Glu Glu Gln Lys Gly 65 70 75 80 Arg Val AlaPhe Ala Ser Asn Phe Leu Ala Gly Asp Ala Ser Leu Gln 85 90 95 Ile Glu ProLeu Lys Pro Ser Asp Glu Gly Arg Tyr Thr Cys Lys Val 100 105 110 Lys AsnSer Gly Arg Tyr Val Trp Ser His Val Ile Leu Lys Val Leu 115 120 125 ValArg Pro Ser Lys Pro Lys Cys Glu Leu Glu Gly Glu Pro Thr Glu 130 135 140Gly Ser Asp Leu Thr Leu Gln Cys Glu Ser Ala Ser Gly Thr Lys Pro 145 150155 160 Ile Val Tyr Tyr Trp Gln Arg Ile Arg Glu Lys Glu Gly Glu Asp Glu165 170 175 His Leu Pro Pro Lys Ser Arg Ile Asp Tyr Asn Asn Pro Gly ArgVal 180 185 190 Leu Leu Gln Asn Leu Thr Met Ala Ser Ser Gly Leu Tyr GlnCys Thr 195 200 205 Ala Gly Asn Glu Ala Gly Lys Glu Ser Cys Val Val ArgVal Thr Val 210 215 220 Gln Tyr Val Gln Ser Ile Gly Met Val Ala Gly AlaVal Thr Gly Ile 225 230 235 240 Val Ala Gly Ala Leu Leu Ile Phe Leu LeuIle Trp Leu Leu Ile Arg 245 250 255 Arg Lys Ser Lys Asp Arg Tyr Glu GluGlu Asp Arg Pro Asn Glu Ile 260 265 270 Arg Glu Asp Ala Glu Ala Pro ArgAla Arg Leu Val Lys Pro Ser Ser 275 280 285 Ser Ser Ser Gly Ser Arg SerSer Arg Ser Gly Ser Ser Ser Thr Arg 290 295 300 Ser Thr Gly Asn Ser AlaSer Arg Ser Gln Arg Thr Leu Ser Ser Glu 305 310 315 320 Ala Ala Pro GlnGln Pro Gly Leu Ala Pro Gln Ala Tyr Ser Leu Ile 325 330 335 Gly Pro GluVal Arg Gly Ser Glu Pro Lys Lys Val His His Thr Thr 340 345 350 Leu ThrLys Ala Glu Thr Thr Leu Ser Thr Thr Pro Ser Gln Ser Lys 355 360 365 AlaPhe Gln Thr Val 370 <210> SEQ ID NO 27 <211> LENGTH: 1332 <212> TYPE:DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: CDS<222> LOCATION: (31)...(1113) <400> SEQUENCE: 27 ccaagaattc ggcacgaggagaggccggcc atg gcc agc ctg ggg ctg ctg ctc 54 Met Ala Ser Leu Gly LeuLeu Leu 1 5 ctg ctc tta ctg aca gca ctg cca ccg ctg tgg tcc tcc tca ctgcct 102 Leu Leu Leu Leu Thr Ala Leu Pro Pro Leu Trp Ser Ser Ser Leu Pro10 15 20 ggg ctg gac act gct gaa agt aaa gcc acc att gca gac ctg atc ctg150 Gly Leu Asp Thr Ala Glu Ser Lys Ala Thr Ile Ala Asp Leu Ile Leu 2530 35 40 tct gcg ctg gag aga gcc acc gtc ttc cta gaa cag agg ctg cct gaa198 Ser Ala Leu Glu Arg Ala Thr Val Phe Leu Glu Gln Arg Leu Pro Glu 4550 55 atc aac ctg gat ggc atg gtg ggg gtc cga gtg ctg gaa gag cag cta246 Ile Asn Leu Asp Gly Met Val Gly Val Arg Val Leu Glu Glu Gln Leu 6065 70 aaa agt gtc cgg gag aag tgg gcc cag gag ccc ctg ctg caa ccg ctg294 Lys Ser Val Arg Glu Lys Trp Ala Gln Glu Pro Leu Leu Gln Pro Leu 7580 85 agc ctg cgc gtg ggg atg ctg ggg gag aag ctg gag gct gcc atc cag342 Ser Leu Arg Val Gly Met Leu Gly Glu Lys Leu Glu Ala Ala Ile Gln 9095 100 aga tcc ctc cac tac ctc aag ctg agt gat ccc aag tac cta aga gag390 Arg Ser Leu His Tyr Leu Lys Leu Ser Asp Pro Lys Tyr Leu Arg Glu 105110 115 120 ttc cag ctg acc ctc cag ccc ggg ttt tgg aag ctc cca cat gcctgg 438 Phe Gln Leu Thr Leu Gln Pro Gly Phe Trp Lys Leu Pro His Ala Trp125 130 135 atc cac act gat gcc tcc ttg gtg tac ccc acg ttc ggg ccc caggac 486 Ile His Thr Asp Ala Ser Leu Val Tyr Pro Thr Phe Gly Pro Gln Asp140 145 150 tca ttc tca gag gag aga agt gac gtg tgc ctg gtg cag ctg ctggga 534 Ser Phe Ser Glu Glu Arg Ser Asp Val Cys Leu Val Gln Leu Leu Gly155 160 165 acc ggg acg gac agc agc gag ccc tgc ggc ctc tca gac ctc tgcagg 582 Thr Gly Thr Asp Ser Ser Glu Pro Cys Gly Leu Ser Asp Leu Cys Arg170 175 180 agc ctc atg acc aag ccc ggc tgc tca ggc tac tgc ctg tcc caccaa 630 Ser Leu Met Thr Lys Pro Gly Cys Ser Gly Tyr Cys Leu Ser His Gln185 190 195 200 ctg ctc ttc ttc ctc tgg gcc aga atg agg ggg tgc aca caggga cca 678 Leu Leu Phe Phe Leu Trp Ala Arg Met Arg Gly Cys Thr Gln GlyPro 205 210 215 ctc caa cag agc cag gac tat atc aac ctc ttc tgc gcc aacatg atg 726 Leu Gln Gln Ser Gln Asp Tyr Ile Asn Leu Phe Cys Ala Asn MetMet 220 225 230 gac ttg aac cgc aga gct gag gcc atc gga tac gcc tac cctacc cgg 774 Asp Leu Asn Arg Arg Ala Glu Ala Ile Gly Tyr Ala Tyr Pro ThrArg 235 240 245 gac atc ttc atg gaa aac atc atg ttc tgt gga atg ggc ggcttc tcc 822 Asp Ile Phe Met Glu Asn Ile Met Phe Cys Gly Met Gly Gly PheSer 250 255 260 gac ttc tac aag ctc cgg tgg ctg gag gcc att ctc agc tggcag aaa 870 Asp Phe Tyr Lys Leu Arg Trp Leu Glu Ala Ile Leu Ser Trp GlnLys 265 270 275 280 cag cag gaa gga tgc ttc ggg gag cct gat gct gaa gatgaa gaa tta 918 Gln Gln Glu Gly Cys Phe Gly Glu Pro Asp Ala Glu Asp GluGlu Leu 285 290 295 tct aaa gct att caa tat cag cag cat ttt tcg agg agagtg aag agg 966 Ser Lys Ala Ile Gln Tyr Gln Gln His Phe Ser Arg Arg ValLys Arg 300 305 310 cga gaa aaa caa ttt cca gat ggc tgc tcc tcc cac aacaca gcc aca 1014 Arg Glu Lys Gln Phe Pro Asp Gly Cys Ser Ser His Asn ThrAla Thr 315 320 325 gca gtg gca gcc ctg ggt ggc ttc cta tac atc ctg gcagaa tac ccc 1062 Ala Val Ala Ala Leu Gly Gly Phe Leu Tyr Ile Leu Ala GluTyr Pro 330 335 340 cca gca aac aga gag cca cac cca tcc aca ccg cca ccacca agc agc 1110 Pro Ala Asn Arg Glu Pro His Pro Ser Thr Pro Pro Pro ProSer Ser 345 350 355 360 cgc tgagacggac ggttccatgc cagctgcctg gaggaggaacagaccccttt 1163 Arg agtcctcatc ccttagatcc tggagggcac ggatcacatcctgggaagaa ggcatctgga 1223 ggataagcaa agccaccccg acacccaatc ttggaagccctgagtaggca gggccagggt 1283 aggtgggggc cgggagggac ccaggtgtga acggatgaataaagttcaa 1332 <210> SEQ ID NO 28 <211> LENGTH: 361 <212> TYPE: PRT<213> ORGANISM: Homo sapiens <400> SEQUENCE: 28 Met Ala Ser Leu Gly LeuLeu Leu Leu Leu Leu Leu Thr Ala Leu Pro 1 5 10 15 Pro Leu Trp Ser SerSer Leu Pro Gly Leu Asp Thr Ala Glu Ser Lys 20 25 30 Ala Thr Ile Ala AspLeu Ile Leu Ser Ala Leu Glu Arg Ala Thr Val 35 40 45 Phe Leu Glu Gln ArgLeu Pro Glu Ile Asn Leu Asp Gly Met Val Gly 50 55 60 Val Arg Val Leu GluGlu Gln Leu Lys Ser Val Arg Glu Lys Trp Ala 65 70 75 80 Gln Glu Pro LeuLeu Gln Pro Leu Ser Leu Arg Val Gly Met Leu Gly 85 90 95 Glu Lys Leu GluAla Ala Ile Gln Arg Ser Leu His Tyr Leu Lys Leu 100 105 110 Ser Asp ProLys Tyr Leu Arg Glu Phe Gln Leu Thr Leu Gln Pro Gly 115 120 125 Phe TrpLys Leu Pro His Ala Trp Ile His Thr Asp Ala Ser Leu Val 130 135 140 TyrPro Thr Phe Gly Pro Gln Asp Ser Phe Ser Glu Glu Arg Ser Asp 145 150 155160 Val Cys Leu Val Gln Leu Leu Gly Thr Gly Thr Asp Ser Ser Glu Pro 165170 175 Cys Gly Leu Ser Asp Leu Cys Arg Ser Leu Met Thr Lys Pro Gly Cys180 185 190 Ser Gly Tyr Cys Leu Ser His Gln Leu Leu Phe Phe Leu Trp AlaArg 195 200 205 Met Arg Gly Cys Thr Gln Gly Pro Leu Gln Gln Ser Gln AspTyr Ile 210 215 220 Asn Leu Phe Cys Ala Asn Met Met Asp Leu Asn Arg ArgAla Glu Ala 225 230 235 240 Ile Gly Tyr Ala Tyr Pro Thr Arg Asp Ile PheMet Glu Asn Ile Met 245 250 255 Phe Cys Gly Met Gly Gly Phe Ser Asp PheTyr Lys Leu Arg Trp Leu 260 265 270 Glu Ala Ile Leu Ser Trp Gln Lys GlnGln Glu Gly Cys Phe Gly Glu 275 280 285 Pro Asp Ala Glu Asp Glu Glu LeuSer Lys Ala Ile Gln Tyr Gln Gln 290 295 300 His Phe Ser Arg Arg Val LysArg Arg Glu Lys Gln Phe Pro Asp Gly 305 310 315 320 Cys Ser Ser His AsnThr Ala Thr Ala Val Ala Ala Leu Gly Gly Phe 325 330 335 Leu Tyr Ile LeuAla Glu Tyr Pro Pro Ala Asn Arg Glu Pro His Pro 340 345 350 Ser Thr ProPro Pro Pro Ser Ser Arg 355 360 <210> SEQ ID NO 29 <211> LENGTH: 1400<212> TYPE: DNA <213> ORGANISM: Mus musculus <220> FEATURE: <221>NAME/KEY: CDS <222> LOCATION: (41)...(1195) <400> SEQUENCE: 29gtcgacccac gcgtccgcat ccaccagcag aaatcctgtc atg gcg aga ctc ggg 55 MetAla Arg Leu Gly 1 5 ctg ctt ctc ctc ctg ctg ctg gcc ctg cca cca cac ttctcc tca gtg 103 Leu Leu Leu Leu Leu Leu Leu Ala Leu Pro Pro His Phe SerSer Val 10 15 20 tca tgg cca gac act gca cag ggc acc atg gca aac ttg atcctg act 151 Ser Trp Pro Asp Thr Ala Gln Gly Thr Met Ala Asn Leu Ile LeuThr 25 30 35 gca tta gaa aaa gcc acc ttg ttc ttg gag gac agg ctg ccc acaatc 199 Ala Leu Glu Lys Ala Thr Leu Phe Leu Glu Asp Arg Leu Pro Thr Ile40 45 50 aac ctg gat ggt gtg gtg ggc ttc caa gtg ctg gaa gtg caa ctc cga247 Asn Leu Asp Gly Val Val Gly Phe Gln Val Leu Glu Val Gln Leu Arg 5560 65 gga gtt cag gaa aaa tgg gct cac aag ccc ttg ctg cag cct ctc agc295 Gly Val Gln Glu Lys Trp Ala His Lys Pro Leu Leu Gln Pro Leu Ser 7075 80 85 atg cgc gct gga cag atg gcc aac aca ctg tct gct ctc ctc caa aaa343 Met Arg Ala Gly Gln Met Ala Asn Thr Leu Ser Ala Leu Leu Gln Lys 9095 100 tcc atc ttc tac ctc aag cag agt gac ccc acg tac cta aga gag ttc391 Ser Ile Phe Tyr Leu Lys Gln Ser Asp Pro Thr Tyr Leu Arg Glu Phe 105110 115 cag cca agc att cag cct ggg ttt tgg aag ttg ccc aat gac tgg aca439 Gln Pro Ser Ile Gln Pro Gly Phe Trp Lys Leu Pro Asn Asp Trp Thr 120125 130 cgc acc aat gcc tcc cta gtc tac ccc tgg ctg gaa ccc ctg gac tct487 Arg Thr Asn Ala Ser Leu Val Tyr Pro Trp Leu Glu Pro Leu Asp Ser 135140 145 ttc tca gag gaa agc agc gat gtg tgc ctg gtg caa cta cta gga aca535 Phe Ser Glu Glu Ser Ser Asp Val Cys Leu Val Gln Leu Leu Gly Thr 150155 160 165 ggg aca gac agc agc cag cct tgc agg ctc tcc aac ttc tgc agaacc 583 Gly Thr Asp Ser Ser Gln Pro Cys Arg Leu Ser Asn Phe Cys Arg Thr170 175 180 ctt atg acc aag gcc ggc tgc tca ggc tac agc ctc tcc cat cagctg 631 Leu Met Thr Lys Ala Gly Cys Ser Gly Tyr Ser Leu Ser His Gln Leu185 190 195 ctc ttc ttc ctc tgg gcc aga atg caa ggg tgc acg gag gga ctgttc 679 Leu Phe Phe Leu Trp Ala Arg Met Gln Gly Cys Thr Glu Gly Leu Phe200 205 210 ctc cag agc caa cac tac atg gac atc ttc tgt gcc aat atg atggaa 727 Leu Gln Ser Gln His Tyr Met Asp Ile Phe Cys Ala Asn Met Met Glu215 220 225 ctg aac cac aga gct gag gcc gtt gga tac gct tac ccc acc caagac 775 Leu Asn His Arg Ala Glu Ala Val Gly Tyr Ala Tyr Pro Thr Gln Asp230 235 240 245 ctc ttc atg gaa aac att atg ttc tgt ggt atg gct ggc ttctct gac 823 Leu Phe Met Glu Asn Ile Met Phe Cys Gly Met Ala Gly Phe SerAsp 250 255 260 ttc tac aag ctg cgc tgg ctg gag gcc att ctc agc tgg cagaac ccc 871 Phe Tyr Lys Leu Arg Trp Leu Glu Ala Ile Leu Ser Trp Gln AsnPro 265 270 275 cag gtg gga tgc ttc ggg agg cct gac aca aag ggt gaa ccttct gaa 919 Gln Val Gly Cys Phe Gly Arg Pro Asp Thr Lys Gly Glu Pro SerGlu 280 285 290 gtt cca cat cag cag ggc att ctg aga aga gtg cga agg cgggaa aaa 967 Val Pro His Gln Gln Gly Ile Leu Arg Arg Val Arg Arg Arg GluLys 295 300 305 ctg ttc gca gat ggc tgt tcg tgc cac aac aca gcc aca gcagtc gca 1015 Leu Phe Ala Asp Gly Cys Ser Cys His Asn Thr Ala Thr Ala ValAla 310 315 320 325 gcc ctg ggt ggc ttt ctc tac atc ctg gca gaa tac caccca gac aat 1063 Ala Leu Gly Gly Phe Leu Tyr Ile Leu Ala Glu Tyr His ProAsp Asn 330 335 340 gga gat gca cat cca gaa tac tac cca aac cat gga gatcca tac tca 1111 Gly Asp Ala His Pro Glu Tyr Tyr Pro Asn His Gly Asp ProTyr Ser 345 350 355 tcc tca cag tca cca gca agc aac tac caa gat ggt gctgcc ggc cct 1159 Ser Ser Gln Ser Pro Ala Ser Asn Tyr Gln Asp Gly Ala AlaGly Pro 360 365 370 gac gtc cag agg act ggc agg ccc ctt agt gtt tcttaagtcctga 1205 Asp Val Gln Arg Thr Gly Arg Pro Leu Ser Val Ser 375 380385 gtcagaggtc acaggctgag gaggcaattg aggaaagtga ccagctatat ccccatcgcc1265 acttctgggt gtttaaaagt cttgggagag cagggccagg gaaagcaggg ttggagagtg1325 gggtggccca gatgtcagca gaatacataa agcacagtca attggagctg aaaaaaaaaa1385 aaaaagggcg gccgc 1400 <210> SEQ ID NO 30 <211> LENGTH: 385 <212>TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 30 Met Ala ArgLeu Gly Leu Leu Leu Leu Leu Leu Leu Ala Leu Pro Pro 1 5 10 15 His PheSer Ser Val Ser Trp Pro Asp Thr Ala Gln Gly Thr Met Ala 20 25 30 Asn LeuIle Leu Thr Ala Leu Glu Lys Ala Thr Leu Phe Leu Glu Asp 35 40 45 Arg LeuPro Thr Ile Asn Leu Asp Gly Val Val Gly Phe Gln Val Leu 50 55 60 Glu ValGln Leu Arg Gly Val Gln Glu Lys Trp Ala His Lys Pro Leu 65 70 75 80 LeuGln Pro Leu Ser Met Arg Ala Gly Gln Met Ala Asn Thr Leu Ser 85 90 95 AlaLeu Leu Gln Lys Ser Ile Phe Tyr Leu Lys Gln Ser Asp Pro Thr 100 105 110Tyr Leu Arg Glu Phe Gln Pro Ser Ile Gln Pro Gly Phe Trp Lys Leu 115 120125 Pro Asn Asp Trp Thr Arg Thr Asn Ala Ser Leu Val Tyr Pro Trp Leu 130135 140 Glu Pro Leu Asp Ser Phe Ser Glu Glu Ser Ser Asp Val Cys Leu Val145 150 155 160 Gln Leu Leu Gly Thr Gly Thr Asp Ser Ser Gln Pro Cys ArgLeu Ser 165 170 175 Asn Phe Cys Arg Thr Leu Met Thr Lys Ala Gly Cys SerGly Tyr Ser 180 185 190 Leu Ser His Gln Leu Leu Phe Phe Leu Trp Ala ArgMet Gln Gly Cys 195 200 205 Thr Glu Gly Leu Phe Leu Gln Ser Gln His TyrMet Asp Ile Phe Cys 210 215 220 Ala Asn Met Met Glu Leu Asn His Arg AlaGlu Ala Val Gly Tyr Ala 225 230 235 240 Tyr Pro Thr Gln Asp Leu Phe MetGlu Asn Ile Met Phe Cys Gly Met 245 250 255 Ala Gly Phe Ser Asp Phe TyrLys Leu Arg Trp Leu Glu Ala Ile Leu 260 265 270 Ser Trp Gln Asn Pro GlnVal Gly Cys Phe Gly Arg Pro Asp Thr Lys 275 280 285 Gly Glu Pro Ser GluVal Pro His Gln Gln Gly Ile Leu Arg Arg Val 290 295 300 Arg Arg Arg GluLys Leu Phe Ala Asp Gly Cys Ser Cys His Asn Thr 305 310 315 320 Ala ThrAla Val Ala Ala Leu Gly Gly Phe Leu Tyr Ile Leu Ala Glu 325 330 335 TyrHis Pro Asp Asn Gly Asp Ala His Pro Glu Tyr Tyr Pro Asn His 340 345 350Gly Asp Pro Tyr Ser Ser Ser Gln Ser Pro Ala Ser Asn Tyr Gln Asp 355 360365 Gly Ala Ala Gly Pro Asp Val Gln Arg Thr Gly Arg Pro Leu Ser Val 370375 380 Ser 385 <210> SEQ ID NO 31 <211> LENGTH: 1239 <212> TYPE: DNA<213> ORGANISM: Homo sapiens <400> SEQUENCE: 31 ctcacaggag gagttggcggggagccttgg gcccctctgg cctcagccgg atttcccagc 60 caaacgcaga gagagatgccctggaccatc ttgctctttg cagctggctc cttggcgatc 120 ccagcaccat ccatccggctggtgcccccg tacccaagca gccaagagga ccccatccac 180 atcgcatgca tggcccctgggaacttcccg ggggcgaatt tcacactgta tcgagggggg 240 caggtggtcc agctcctgcaggcccccacg gaccagcgcg gggtgacatt taacctgagc 300 ggcggcagca gcaaggctccagggggaccc ttccactgcc agtatggagt gttaggtgag 360 ctcaaccagt cccagctgtcagacctcagc gagcccgtga acgtctcctt cccagtgccc 420 acttggatct tggtgctctccctgagcctg gctggtgccc tcttcctcct tgctgggctg 480 gtggctgttg ccctggtggtcagaaaagtt aaactcagaa atttacagaa gaaaagagat 540 cgagaatcct gctgggcccagattaacttc gacagcacag acatgtcctt cgataactcc 600 ctgtttaccg tctccgcgaaaacgatgcca gaagaagacc cggccacctt ggatgatcac 660 tcaggcacca ctgccacccccagcaactcc aggacccgga agaggcccac ttccacgtcc 720 tcctcgcctg agacccccgaattcagcact ttccgggcct gccagtgagg ctgaggactg 780 ggggacccct ctgtctccaggcattcgggg gcctgaggtc cctccagcta cttctggggg 840 ggctctgtca gccactttctcagggaattg gacagaggaa aggaagggga accctggcct 900 tgggattttc atcacagaggagtgggagag gggacacagg catgggcctg gcactataca 960 gacaacagga agttcccctctcgaccttcg gctcctcagg accaccagag aaggagatgt 1020 caggacccct tcttgtcccccagctgggcc ataagacgtc ccaggtctct gcacacccgt 1080 ggaattcctc ccttccccagtgggtttttg agcatagggt gcccttgggt gtgttgtgtg 1140 tctgcctgct ggcttgcttaagttattaat tataacacgg gtcaaggtgt taaaaaaaaa 1200 aaaaaaaaaa aaaaaaaaaaaaaaaaaaaa aaaaaaaaa 1239 <210> SEQ ID NO 32 <211> LENGTH: 230 <212>TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 32 Met Pro TrpThr Ile Leu Leu Phe Ala Ala Gly Ser Leu Ala Ile Pro 1 5 10 15 Ala ProSer Ile Arg Leu Val Pro Pro Tyr Pro Ser Ser Gln Glu Asp 20 25 30 Pro IleHis Ile Ala Cys Met Ala Pro Gly Asn Phe Pro Gly Ala Asn 35 40 45 Phe ThrLeu Tyr Arg Gly Gly Gln Val Val Gln Leu Leu Gln Ala Pro 50 55 60 Thr AspGln Arg Gly Val Thr Phe Asn Leu Ser Gly Gly Ser Ser Lys 65 70 75 80 AlaPro Gly Gly Pro Phe His Cys Gln Tyr Gly Val Leu Gly Glu Leu 85 90 95 AsnGln Ser Gln Leu Ser Asp Leu Ser Glu Pro Val Asn Val Ser Phe 100 105 110Pro Val Pro Thr Trp Ile Leu Val Leu Ser Leu Ser Leu Ala Gly Ala 115 120125 Leu Phe Leu Leu Ala Gly Leu Val Ala Val Ala Leu Val Val Arg Lys 130135 140 Val Lys Leu Arg Asn Leu Gln Lys Lys Arg Asp Arg Glu Ser Cys Trp145 150 155 160 Ala Gln Ile Asn Phe Asp Ser Thr Asp Met Ser Phe Asp AsnSer Leu 165 170 175 Phe Thr Val Ser Ala Lys Thr Met Pro Glu Glu Asp ProAla Thr Leu 180 185 190 Asp Asp His Ser Gly Thr Thr Ala Thr Pro Ser AsnSer Arg Thr Arg 195 200 205 Lys Arg Pro Thr Ser Thr Ser Ser Ser Pro GluThr Pro Glu Phe Ser 210 215 220 Thr Phe Arg Ala Cys Gln 225 230 <210>SEQ ID NO 33 <211> LENGTH: 1778 <212> TYPE: DNA <213> ORGANISM: Homosapiens <400> SEQUENCE: 33 cgactttcag tccccgacgc gccccgccca acccctacgatgaagagggc gtccgctgga 60 gggagccggc tgctggcatg ggtgctgtgg ctgcaggcctggcaggtggc agccccatgc 120 ccaggtgcct gcgtatgcta caatgagccc aaggtgacgacaagctgccc ccagcagggc 180 ctgcaggctg tgcccgtggg catccctgct gccagccagcgcatcttcct gcacggcaac 240 cgcatctcgc atgtgccagc tgccagcttc cgtgcctgccgcaacctcac catcctgtgg 300 ctgcactcga atgtgctggc ccgaattgat gcggctgccttcactggcct ggccctcctg 360 gagcagctgg acctcagcga taatgcacag ctccggtctgtggaccctgc cacattccac 420 ggcctgggcc gcgtacacac gctgcacctg gaccgctgcggcctgcagga gctgggcccg 480 gggctgttcc gcggcctggc tgccctgcag tacctctacctgcaggacaa cgcgctgcag 540 gcactgcctg atgacacctt ccgcgacctg ggcaacctcacacacctctt cctgcacggc 600 aaccgcatct ccagcgtgcc cgagcgcgcc ttccgtgggctgcacagcct cgaccgtctc 660 ctactgcacc agaaccgcgt ggcccatgtg cacccgcatgccttccgtga ccttggccgc 720 ctcatgacac tctatctgtt tgccaacaat ctatcagcgctgcccactga ggccctggcc 780 cccctgcgtg ccctgcagta cctgaggctc aacgacaacccctgggtgtg tgactgccgg 840 gcacgcccac tctgggcctg gctgcagaag ttccgcggctcctcctccga ggtgccctgc 900 agcctcccgc aacgcctggc tggccgtgac ctcaaacgcctagctgccaa tgacctgcag 960 ggctgcgctg tggccaccgg cccttaccat cccatctggaccggcagggc caccgatgag 1020 gagccgctgg ggcttcccaa gtgctgccag ccagatgccgctgacaaggc ctcagtactg 1080 gagcctggaa gaccagcttc ggcaggcaat gcgctgaagggacgcgtgcc gcccggtgac 1140 agcccgccgg gcaacggctc tggcccacgg cacatcaatgactcaccctt tgggactctg 1200 cctggctctg ctgagccccc gctcactgca gtgcggcccgagggctccga gccaccaggg 1260 ttccccacct cgggccctcg ccggaggcca ggctgttcacgcaagaaccg cacccgcagc 1320 cactgccgtc tgggccaggc aggcagcggg ggtggcgggactggtgactc agaaggctca 1380 ggtgccctac ccagcctcac ctgcagcctc acccccctgggcctggcgct ggtgctgtgg 1440 acagtgcttg ggccctgctg acccccagcg gacacaagagcgtgctcagc agccaggtgt 1500 gtgtacatac ggggtctctc tccacgccgc caagccagccgggcggccga cccgtggggc 1560 aggccaggcc aggtcctccc tgatggacgc ctgccgcccgccacccccat ctccacccca 1620 tcatgtttac agggttcggc ggcagcgttt gttccagaacgccgcctccc acccagatcg 1680 cggtatatag agatatgcat tttattttac ttgtggaaaaatatcggacg acgtggaata 1740 aagagctctt ttcttaaaaa aaaaaaaaaa aaaaaaaa1778 <210> SEQ ID NO 34 <211> LENGTH: 473 <212> TYPE: PRT <213>ORGANISM: Homo sapiens <400> SEQUENCE: 34 Met Lys Arg Ala Ser Ala GlyGly Ser Arg Leu Leu Ala Trp Val Leu 1 5 10 15 Trp Leu Gln Ala Trp GlnVal Ala Ala Pro Cys Pro Gly Ala Cys Val 20 25 30 Cys Tyr Asn Glu Pro LysVal Thr Thr Ser Cys Pro Gln Gln Gly Leu 35 40 45 Gln Ala Val Pro Val GlyIle Pro Ala Ala Ser Gln Arg Ile Phe Leu 50 55 60 His Gly Asn Arg Ile SerHis Val Pro Ala Ala Ser Phe Arg Ala Cys 65 70 75 80 Arg Asn Leu Thr IleLeu Trp Leu His Ser Asn Val Leu Ala Arg Ile 85 90 95 Asp Ala Ala Ala PheThr Gly Leu Ala Leu Leu Glu Gln Leu Asp Leu 100 105 110 Ser Asp Asn AlaGln Leu Arg Ser Val Asp Pro Ala Thr Phe His Gly 115 120 125 Leu Gly ArgVal His Thr Leu His Leu Asp Arg Cys Gly Leu Gln Glu 130 135 140 Leu GlyPro Gly Leu Phe Arg Gly Leu Ala Ala Leu Gln Tyr Leu Tyr 145 150 155 160Leu Gln Asp Asn Ala Leu Gln Ala Leu Pro Asp Asp Thr Phe Arg Asp 165 170175 Leu Gly Asn Leu Thr His Leu Phe Leu His Gly Asn Arg Ile Ser Ser 180185 190 Val Pro Glu Arg Ala Phe Arg Gly Leu His Ser Leu Asp Arg Leu Leu195 200 205 Leu His Gln Asn Arg Val Ala His Val His Pro His Ala Phe ArgAsp 210 215 220 Leu Gly Arg Leu Met Thr Leu Tyr Leu Phe Ala Asn Asn LeuSer Ala 225 230 235 240 Leu Pro Thr Glu Ala Leu Ala Pro Leu Arg Ala LeuGln Tyr Leu Arg 245 250 255 Leu Asn Asp Asn Pro Trp Val Cys Asp Cys ArgAla Arg Pro Leu Trp 260 265 270 Ala Trp Leu Gln Lys Phe Arg Gly Ser SerSer Glu Val Pro Cys Ser 275 280 285 Leu Pro Gln Arg Leu Ala Gly Arg AspLeu Lys Arg Leu Ala Ala Asn 290 295 300 Asp Leu Gln Gly Cys Ala Val AlaThr Gly Pro Tyr His Pro Ile Trp 305 310 315 320 Thr Gly Arg Ala Thr AspGlu Glu Pro Leu Gly Leu Pro Lys Cys Cys 325 330 335 Gln Pro Asp Ala AlaAsp Lys Ala Ser Val Leu Glu Pro Gly Arg Pro 340 345 350 Ala Ser Ala GlyAsn Ala Leu Lys Gly Arg Val Pro Pro Gly Asp Ser 355 360 365 Pro Pro GlyAsn Gly Ser Gly Pro Arg His Ile Asn Asp Ser Pro Phe 370 375 380 Gly ThrLeu Pro Gly Ser Ala Glu Pro Pro Leu Thr Ala Val Arg Pro 385 390 395 400Glu Gly Ser Glu Pro Pro Gly Phe Pro Thr Ser Gly Pro Arg Arg Arg 405 410415 Pro Gly Cys Ser Arg Lys Asn Arg Thr Arg Ser His Cys Arg Leu Gly 420425 430 Gln Ala Gly Ser Gly Gly Gly Gly Thr Gly Asp Ser Glu Gly Ser Gly435 440 445 Ala Leu Pro Ser Leu Thr Cys Ser Leu Thr Pro Leu Gly Leu AlaLeu 450 455 460 Val Leu Trp Thr Val Leu Gly Pro Cys 465 470 <210> SEQ IDNO 35 <211> LENGTH: 1946 <212> TYPE: DNA <213> ORGANISM: Homo sapiens<400> SEQUENCE: 35 cgcgctgcga gcgccccgcc agtccgcgcc gccgccctcaccctgtgcgc ccgcagcccg 60 cgagcccagc ccggcccggt agagcggagc gccggagcctcgtcccgcgg ccgggccggg 120 accgggccgg agcagcggcg cctggatgcg gacccggccgcgcgcagacg ggcgcccgcc 180 ccgaagccgc ttccagtgcc cgacgcgccc cgctcgaccccgaagatgaa gagggcgtcc 240 tccggaggaa gcaggctgct ggcatgggtg ttatggctacaggcctggag ggtagcaaca 300 ccatgccctg gtgcttgtgt gtgctacaat gagcccaaggtaacaacaag ctgcccccag 360 cagggtctgc aggctgtgcc cactggcatc ccagcctctagccagcgaat cttcctgcat 420 ggcaaccgaa tctctcacgt gccagctgcg agcttccagtcatgccgaaa tctcactatc 480 ctgtggctgc actctaatgc gctggctcgg atcgatgctgctgccttcac tggtctgacc 540 ctcctggagc aactagatct tagtgataat gcacagcttcatgtcgtgga ccctaccacg 600 ttccacggcc tgggccacct gcacacactg cacctagaccgatgtggcct gcgggagctg 660 ggtcccggcc tattccgtgg actagcagct ctgcagtacctctacctaca agacaacaat 720 ctgcaggcac tccctgacaa cacctttcga gacctgggcaacctcacgca tctctttctg 780 catggcaacc gtatccccag tgtgcctgag cacgctttccgtggcctgca cagtcttgac 840 cgcctcctct tgcaccagaa ccatgtggct cgtgtgcacccacatgcctt ccgggacctt 900 ggccgcctca tgaccctcta cctgtttgcc aacaacctctccatgctgcc tgcagaggtc 960 ctaatgcccc tgaggtctct gcagtacctg cgactcaatgacaacccctg ggtgtgtgac 1020 tgccgggcac gtccactctg ggcctggctg cagaagttccgaggttcctc atcagaggtg 1080 ccctgcaacc tgccccaacg cctggcagac cgtgatcttaagcgcctcgc tgccagtgac 1140 ctagagggct gtgctgtggc ttcaggaccc ttccgtcccatccagaccag tcagctcact 1200 gatgaggagc tgctgagcct ccccaagtgc tgccagccagatgctgcaga caaagcctca 1260 gtactggaac ccgggaggcc agcttctgcc ggaaacgccctcaagggacg tgtgcctccc 1320 ggtgacactc caccaggcaa tggctcaggc cctcggcacatcaatgactc tccatttgga 1380 actttgccca gctctgcaga gcccccactg actgccctgcggcctggggg ttccgagcca 1440 ccaggacttc ccaccactgg tccccgcagg aggccaggttgttcccggaa gaatcgcacc 1500 cgcagccact gccgtctggg ccaggcggga agtggggccagtggaacagg ggacgcagag 1560 ggttcagggg ctctgcctgc tctggcctgc agccttgctcctctgggcct tgcactggta 1620 ctttggacag tgcttgggcc ctgctgacca gccaccagccaccaggtgtg tgtacatatg 1680 gggtctccct ccacgccgcc agccagagcc agggacaggctctgaggggc aggccaggcc 1740 ctccctgaca gatgcctccc caccagccca cccccatctccaccccatca tgtttacagg 1800 gttccggggg tggcgtttgt tccagaacgc cacctcccacccggatcgcg gtatatagag 1860 atatgaattt tattttactt gtgtaaaata tcggatgacgtggaataaag agctcttttc 1920 ttaaaaaaaa aaaaaaaaaa aaaaaa 1946 <210> SEQID NO 36 <211> LENGTH: 473 <212> TYPE: PRT <213> ORGANISM: Mus musculus<400> SEQUENCE: 36 Met Lys Arg Ala Ser Ser Gly Gly Ser Arg Leu Leu AlaTrp Val Leu 1 5 10 15 Trp Leu Gln Ala Trp Arg Val Ala Thr Pro Cys ProGly Ala Cys Val 20 25 30 Cys Tyr Asn Glu Pro Lys Val Thr Thr Ser Cys ProGln Gln Gly Leu 35 40 45 Gln Ala Val Pro Thr Gly Ile Pro Ala Ser Ser GlnArg Ile Phe Leu 50 55 60 His Gly Asn Arg Ile Ser His Val Pro Ala Ala SerPhe Gln Ser Cys 65 70 75 80 Arg Asn Leu Thr Ile Leu Trp Leu His Ser AsnAla Leu Ala Arg Ile 85 90 95 Asp Ala Ala Ala Phe Thr Gly Leu Thr Leu LeuGlu Gln Leu Asp Leu 100 105 110 Ser Asp Asn Ala Gln Leu His Val Val AspPro Thr Thr Phe His Gly 115 120 125 Leu Gly His Leu His Thr Leu His LeuAsp Arg Cys Gly Leu Arg Glu 130 135 140 Leu Gly Pro Gly Leu Phe Arg GlyLeu Ala Ala Leu Gln Tyr Leu Tyr 145 150 155 160 Leu Gln Asp Asn Asn LeuGln Ala Leu Pro Asp Asn Thr Phe Arg Asp 165 170 175 Leu Gly Asn Leu ThrHis Leu Phe Leu His Gly Asn Arg Ile Pro Ser 180 185 190 Val Pro Glu HisAla Phe Arg Gly Leu His Ser Leu Asp Arg Leu Leu 195 200 205 Leu His GlnAsn His Val Ala Arg Val His Pro His Ala Phe Arg Asp 210 215 220 Leu GlyArg Leu Met Thr Leu Tyr Leu Phe Ala Asn Asn Leu Ser Met 225 230 235 240Leu Pro Ala Glu Val Leu Met Pro Leu Arg Ser Leu Gln Tyr Leu Arg 245 250255 Leu Asn Asp Asn Pro Trp Val Cys Asp Cys Arg Ala Arg Pro Leu Trp 260265 270 Ala Trp Leu Gln Lys Phe Arg Gly Ser Ser Ser Glu Val Pro Cys Asn275 280 285 Leu Pro Gln Arg Leu Ala Asp Arg Asp Leu Lys Arg Leu Ala AlaSer 290 295 300 Asp Leu Glu Gly Cys Ala Val Ala Ser Gly Pro Phe Arg ProIle Gln 305 310 315 320 Thr Ser Gln Leu Thr Asp Glu Glu Leu Leu Ser LeuPro Lys Cys Cys 325 330 335 Gln Pro Asp Ala Ala Asp Lys Ala Ser Val LeuGlu Pro Gly Arg Pro 340 345 350 Ala Ser Ala Gly Asn Ala Leu Lys Gly ArgVal Pro Pro Gly Asp Thr 355 360 365 Pro Pro Gly Asn Gly Ser Gly Pro ArgHis Ile Asn Asp Ser Pro Phe 370 375 380 Gly Thr Leu Pro Ser Ser Ala GluPro Pro Leu Thr Ala Leu Arg Pro 385 390 395 400 Gly Gly Ser Glu Pro ProGly Leu Pro Thr Thr Gly Pro Arg Arg Arg 405 410 415 Pro Gly Cys Ser ArgLys Asn Arg Thr Arg Ser His Cys Arg Leu Gly 420 425 430 Gln Ala Gly SerGly Ala Ser Gly Thr Gly Asp Ala Glu Gly Ser Gly 435 440 445 Ala Leu ProAla Leu Ala Cys Ser Leu Ala Pro Leu Gly Leu Ala Leu 450 455 460 Val LeuTrp Thr Val Leu Gly Pro Cys 465 470 <210> SEQ ID NO 37 <211> LENGTH:1348 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 37gccaaagaga catatccaag gttgagatta gtttccattt tctttgtact attttctgga 60taataagaca ttagacattt gaagagatgg agaatgaaga tgggtatatg acgctgagtt 120tcaagaatcg ttgtaaatcg aagcagaaat ctaaagattt ctccctatat ccacaatatt 180attgtcttct gctcatattt ggatgcattg tgatccttat attcattatg acagggattg 240acctgaagtt ctggcataaa aaaatggatt tctcccagaa tgtaaacatc agcagtctat 300caggacacaa ttacttgtgc ccaaatgact ggctgttgaa cgaagggaaa tgttactggt 360tttcaacttc ttttaaaacg tggaaagaga gtcaacgtga ttgtacacag ctacaggcac 420atttactggt gattcaaaat ttggatgagc tggagttcat acagaacagt ttaaaacctg 480gacattttgg ttggattgga ctatatgtta cattccaagg gaacctatgg atgtggatag 540atgaacactt tttagttcca gaattgtttt cagtgattgg accaactgat gacaggagct 600gtgccgttat cacaggaaac tgggtgtatt ctgaagactg tagctccaca tttaagggca 660tttgccagag agatgcgatc ttgacgcaca atggaaccag tggtgtgtaa atgtacaacc 720aaatatagaa atactttgca tgttaaagca gagctagatt ttaaagactt aagattttta 780gataaagttt ctaacagaaa gtttctgcta acagacatca tctaaatagg agaaaagtat 840tttatcctga attgactata aagacaactt ctgaacagaa cttttactct atacttggat 900ttctggtttg tcttttccat ggcattgaca agaaaagcta aataaaaaat tagtaattat 960tttaatagtt atttaatagt ttgatttttt tgcatttaaa atagcataga ataaaacaac 1020tttaaaggaa tgttatttag ctatatgtgc tatgtggtag attggaagga aagaagcagt 1080atatgtacaa atataatatt tgaagcatgg aattctgaat ttttcatctg tgtattatag 1140cctgaagtgt ttggtgggga gtgggtaatg agaaattacc tactgggtat aatgtacaat 1200atttaggtga tggataaact aaaagctcag acttctccac tttgtgatat atccatgtaa 1260caaaattatg cttgtaccct ttaaatgtat tcaaataaaa taaaataaag tcatgtggcc 1320aaatattcaa aacaaaaaaa aaaaaaaa 1348 <210> SEQ ID NO 38 <211> LENGTH: 207<212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 38 Met GluAsn Glu Asp Gly Tyr Met Thr Leu Ser Phe Lys Asn Arg Cys 1 5 10 15 LysSer Lys Gln Lys Ser Lys Asp Phe Ser Leu Tyr Pro Gln Tyr Tyr 20 25 30 CysLeu Leu Leu Ile Phe Gly Cys Ile Val Ile Leu Ile Phe Ile Met 35 40 45 ThrGly Ile Asp Leu Lys Phe Trp His Lys Lys Met Asp Phe Ser Gln 50 55 60 AsnVal Asn Ile Ser Ser Leu Ser Gly His Asn Tyr Leu Cys Pro Asn 65 70 75 80Asp Trp Leu Leu Asn Glu Gly Lys Cys Tyr Trp Phe Ser Thr Ser Phe 85 90 95Lys Thr Trp Lys Glu Ser Gln Arg Asp Cys Thr Gln Leu Gln Ala His 100 105110 Leu Leu Val Ile Gln Asn Leu Asp Glu Leu Glu Phe Ile Gln Asn Ser 115120 125 Leu Lys Pro Gly His Phe Gly Trp Ile Gly Leu Tyr Val Thr Phe Gln130 135 140 Gly Asn Leu Trp Met Trp Ile Asp Glu His Phe Leu Val Pro GluLeu 145 150 155 160 Phe Ser Val Ile Gly Pro Thr Asp Asp Arg Ser Cys AlaVal Ile Thr 165 170 175 Gly Asn Trp Val Tyr Ser Glu Asp Cys Ser Ser ThrPhe Lys Gly Ile 180 185 190 Cys Gln Arg Asp Ala Ile Leu Thr His Asn GlyThr Ser Gly Val 195 200 205 <210> SEQ ID NO 39 <211> LENGTH: 3345 <212>TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 39 ggggggcgcaggaccctcgc aacttcttcg caggactcca gcctggccgc cggcgcccgc 60 agccgtccgagagccctgcg cccgcgcctc cccttgcgca ccgtggcagc gcccggcggg 120 cggtcctgccagccccgacg ggatgcccgc agccatgctc ccctacgctt gcgtcctggt 180 gcttttgggagcccacactg caccggcggc tggggaggcc gggggcagct gcctgcgctg 240 ggaaccccactgccagcagc ccttgccaga tagagtgccc agcactgcga tcctgcctcc 300 acgccttaatggaccttgga tctccacagg ccggctcttt cgagcccacc agttctacta 360 cgaggaccccttctgcgggg aacctgccca ctcgctgctc gtcaagggca aagtccgcct 420 gcgccgggcctcctgggtca cccggggagc caccgaggcc gactaccacc tgcacaaggt 480 gggcatcgtcttccacagcc gccgggccct ggtcgacgtc accgggcgcc tcaaccagac 540 ccgcgccggccgggactgcg cgcggcggct gcctccggcc cgggcctggc tgcctggggc 600 gctgtacgagctgcggagcg cccgggctca gggggactgc ctggaggcgc tgggcctcac 660 catgcacgagctcagcctgg tccgcgtgca gcgccgcctg cagccgcagc cccgggcgtc 720 gccccggctggtggaggagc tgtacctggg ggacatccac accgacccgg cggagaggcg 780 gcactaccggcccacgggct accagcgccc gctgcagagc gcactgcacc acgtgcagcc 840 gtgcccagcctgtggcctca ttgcccgctc cgatgtgcac cacccgcccg tgctgccgcc 900 ccctctggccctgcccctgc acctgggcgg ctggtgggtc agctcggggt gcgaggtgcg 960 cccagcagtcctgttcctca cccggctctt cactttccac gggcacagcc gctcctggga 1020 agggtattaccaccacttct cagacccagc ctgccggcag cccaccttca ccgtgtatgc 1080 cgccggccgctacaccaggg gcacgccatc caccagggtc cgcggcggca ccgagctggt 1140 gtttgaggtcacacgggccc atgtgacccc catggaccag gtcaccacgg ccatgctcaa 1200 cttctctgagccaagcagct gtgggggtgc gggggcctgg tccatgggca ctgagcggga 1260 tgtcacagccaccaacggct gcctaccgct gggcatccgg ctcccgcatg tggagtacga 1320 gcttttcaagatggaacaag accccctcgg gcaaagcctg ctcttcatcg gacaaaggcc 1380 caccgatggctcaagtcccg ataccccaga gaaacgtccc acctcctacc aagcacccct 1440 ggtgctctgtcatggggagg cccccgactt ctccaggcca ccgcagcaca ggccatcgct 1500 gcagaagcaccccagcacag ggggtcttca catagccccc ttcccacttc tgcccctagt 1560 tctagggctggccttcctcc actggctatg acattggact tgacatcagg atggcggctc 1620 tggacacccattcaaccctt cagactccct cctggcagct gtagggaagg aaccattctc 1680 ctctgctctgtcatggatgg atgcacagcc ccactgcttc caaactctgc ctgtgtccca 1740 tgtggctcaggacatgagct taacccctgc aaagcctata ccacatccca cagcccgggt 1800 ccccagtcaagcacttggat gcggcagtga tgttcatcgc tacgtgagtt tctaaagatc 1860 actcccaatttttctacttt cctcatcctt ggcagctcgc caacaggtgc agtcaggggg 1920 ccacacggaacacccccatc ccatgttccc cccagttctt cccatcctga cccttgggat 1980 tccaagatgggagcaagagg agatcctgag gctctgccta gggacgaggc ctacagttct 2040 gccatgtctgtaggttgttg tttaaagatt attaattcga atttagcaat acgatctcta 2100 agtggtgccatgaattaaag atgccacttc gggctttcag tgcttctcag cttttgggca 2160 aagggcttgtgtcttcaggg gcagctcagc tttcctgagt cctgactgct ggcattcgtc 2220 tgcatttgcctgtgcttctg cgagtcggac ctcaagctgc caacactgca tgtggataaa 2280 tccagttttcccgggccagc atgcaaaatg aagaggactc catctaagct gagaagcatg 2340 gcctccccagagcagcctgc agcctccaag ccttcctggc ccaggcaaat gccagtgtgc 2400 accaggctggctgctggggg caggtctttg gaggggagca gcatttccag ccttctgaac 2460 atagttaatagtaatgacag ccgtaacact aacgcgctct gcaattcgcc ctgcccagcc 2520 atcctcggttgccaagattg cctgtgcctg cctgacaaag gaagagaatc tccgaatgtg 2580 tatctttgggcccaccctag ggagaggtcg gggtcaccag gctacatggc gacatctagg 2640 cagctccgccttgcccagcc tccttgccat aatcctaata tattggtgtc ctctgctcag 2700 aggggactgtcatcatggtg ggaacaggct gtgcctcccc agggactctg cccatgttcc 2760 cagggcctcatctgtacact gtgaaattaa ctggcatcct ggtgggccca agggttttca 2820 ggactgggggccaatgactc accccctcct tcctcctcct gatccctatc tctagctctt 2880 atcacagattttgaacaatt gtctgtgagg ttaatgatgg tttcagaggg aagccctttt 2940 cctccctgagactgtgtggg gttcagtcag cctgctgaaa ttgcttccac ttattaccca 3000 tccttcctcttaaaaaaaaa aaaaagccca ccaagttagt attctctgta gctctcagac 3060 agctacaagtgttcctggca tatttaccaa agtacaagaa atcattacat tatttacggt 3120 ctcagactacatcagggttg ggggagctcc tggtggggat ggcagtgggt gtcgatgata 3180 tgtccacggctgagcaggtc ttgtatccga agcttgaagt aaccatgcca ccatttatca 3240 tcaaatttgaaccttttaat aaaattaaac agcctgaaaa aaaaaaaaaa aaaaaaaaaa 3300 aaaaaaaaaaaaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaa 3345 <210> SEQ ID NO 40 <211>LENGTH: 482 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE:40 Met Pro Ala Ala Met Leu Pro Tyr Ala Cys Val Leu Val Leu Leu Gly 1 510 15 Ala His Thr Ala Pro Ala Ala Gly Glu Ala Gly Gly Ser Cys Leu Arg 2025 30 Trp Glu Pro His Cys Gln Gln Pro Leu Pro Asp Arg Val Pro Ser Thr 3540 45 Ala Ile Leu Pro Pro Arg Leu Asn Gly Pro Trp Ile Ser Thr Gly Arg 5055 60 Leu Phe Arg Ala His Gln Phe Tyr Tyr Glu Asp Pro Phe Cys Gly Glu 6570 75 80 Pro Ala His Ser Leu Leu Val Lys Gly Lys Val Arg Leu Arg Arg Ala85 90 95 Ser Trp Val Thr Arg Gly Ala Thr Glu Ala Asp Tyr His Leu His Lys100 105 110 Val Gly Ile Val Phe His Ser Arg Arg Ala Leu Val Asp Val ThrGly 115 120 125 Arg Leu Asn Gln Thr Arg Ala Gly Arg Asp Cys Ala Arg ArgLeu Pro 130 135 140 Pro Ala Arg Ala Trp Leu Pro Gly Ala Leu Tyr Glu LeuArg Ser Ala 145 150 155 160 Arg Ala Gln Gly Asp Cys Leu Glu Ala Leu GlyLeu Thr Met His Glu 165 170 175 Leu Ser Leu Val Arg Val Gln Arg Arg LeuGln Pro Gln Pro Arg Ala 180 185 190 Ser Pro Arg Leu Val Glu Glu Leu TyrLeu Gly Asp Ile His Thr Asp 195 200 205 Pro Ala Glu Arg Arg His Tyr ArgPro Thr Gly Tyr Gln Arg Pro Leu 210 215 220 Gln Ser Ala Leu His His ValGln Pro Cys Pro Ala Cys Gly Leu Ile 225 230 235 240 Ala Arg Ser Asp ValHis His Pro Pro Val Leu Pro Pro Pro Leu Ala 245 250 255 Leu Pro Leu HisLeu Gly Gly Trp Trp Val Ser Ser Gly Cys Glu Val 260 265 270 Arg Pro AlaVal Leu Phe Leu Thr Arg Leu Phe Thr Phe His Gly His 275 280 285 Ser ArgSer Trp Glu Gly Tyr Tyr His His Phe Ser Asp Pro Ala Cys 290 295 300 ArgGln Pro Thr Phe Thr Val Tyr Ala Ala Gly Arg Tyr Thr Arg Gly 305 310 315320 Thr Pro Ser Thr Arg Val Arg Gly Gly Thr Glu Leu Val Phe Glu Val 325330 335 Thr Arg Ala His Val Thr Pro Met Asp Gln Val Thr Thr Ala Met Leu340 345 350 Asn Phe Ser Glu Pro Ser Ser Cys Gly Gly Ala Gly Ala Trp SerMet 355 360 365 Gly Thr Glu Arg Asp Val Thr Ala Thr Asn Gly Cys Leu ProLeu Gly 370 375 380 Ile Arg Leu Pro His Val Glu Tyr Glu Leu Phe Lys MetGlu Gln Asp 385 390 395 400 Pro Leu Gly Gln Ser Leu Leu Phe Ile Gly GlnArg Pro Thr Asp Gly 405 410 415 Ser Ser Pro Asp Thr Pro Glu Lys Arg ProThr Ser Tyr Gln Ala Pro 420 425 430 Leu Val Leu Cys His Gly Glu Ala ProAsp Phe Ser Arg Pro Pro Gln 435 440 445 His Arg Pro Ser Leu Gln Lys HisPro Ser Thr Gly Gly Leu His Ile 450 455 460 Ala Pro Phe Pro Leu Leu ProLeu Val Leu Gly Leu Ala Phe Leu His 465 470 475 480 Trp Leu <210> SEQ IDNO 41 <211> LENGTH: 3575 <212> TYPE: DNA <213> ORGANISM: Homo sapiens<400> SEQUENCE: 41 gcttcccgag gctccgcacc agccgcgctt ctgtccgcctgcagggcatt ccagaaagat 60 gaggatattt gctgtcttta tattcatgac ctactggcatttgctgaacg catttactgt 120 cacggttccc aaggacctat atgtggtaga gtatggtagcaatatgacaa ttgaatgcaa 180 attcccagta gaaaaacaat tagacctggc tgcactaattgtctattggg aaatggagga 240 taagaacatt attcaatttg tgcatggaga ggaagacctgaaggttcagc atagtagcta 300 cagacagagg gcccggctgt tgaaggacca gctctccctgggaaatgctg cacttcagat 360 cacagatgtg aaattgcagg atgcaggggt gtaccgctgcatgatcagct atggtggtgc 420 cgactacaag cgaattactg tgaaagtcaa tgccccatacaacaaaatca accaaagaat 480 tttggttgtg gatccagtca cctctgaaca tgaactgacatgtcaggctg agggctaccc 540 caaggccgaa gtcatctgga caagcagtga ccatcaagtcctgagtggta agaccaccac 600 caccaattcc aagagagagg agaagctttt caatgtgaccagcacactga gaatcaacac 660 aacaactaat gagattttct actgcacttt taggagattagatcctgagg aaaaccatac 720 agctgaattg gtcatcccag aactacctct ggcacatcctccaaatgaaa ggactcactt 780 ggtaattctg ggagccatct tattatgcct tggtgtagcactgacattca tcttccgttt 840 aagaaaaggg agaatgatgg atgtgaaaaa atgtggcatccaagatacaa actcaaagaa 900 gcaaagtgat acacatttgg aggagacgta atccagcattggaacttctg atcttcaagc 960 agggattctc aacctgtggt ttaggggttc atcggggctgagcgtgacaa gaggaaggaa 1020 tgggcccgtg ggatgcaggc aatgtgggac ttaaaaggcccaagcactga aaatggaacc 1080 tggcgaaagc agaggaggag aatgaagaaa gatggagtcaaacagggagc ctggagggag 1140 accttgatac tttcaaatgc ctgaggggct catcgacgcctgtgacaggg agaaaggata 1200 cttctgaaca aggagcctcc aagcaaatca tccattgctcatcctaggaa gacgggttga 1260 gaatccctaa tttgagggtc agttcctgca gaagtgccctttgcctccac tcaatgcctc 1320 aatttgtttt ctgcatgact gagagtctca gtgttggaacgggacagtat ttatgtatga 1380 gtttttccta tttattttga gtctgtgagg tcttcttgtcatgtgagtgt ggttgtgaat 1440 gatttctttt gaagatatat tgtagtagat gttacaattttgtcgccaaa ctaaacttgc 1500 tgcttaatga tttgctcaca tctagtaaaa catggagtatttgtaaggtg cttggtctcc 1560 tctataacta caagtataca ttggaagcat aaagatcaaaccgttggttg cataggatgt 1620 cacctttatt taacccatta atactctggt tgacctaatcttattctcag acctcaagtg 1680 tctgtgcagt atctgttcca tttaaatatc agctttacaattatgtggta gcctacacac 1740 ataatctcat ttcatcgctg taaccaccct gttgtgataaccactattat tttacccatc 1800 gtacagctga ggaagcaaac agattaagta acttgcccaaaccagtaaat agcagacctc 1860 agactgccac ccactgtcct tttataatac aatttacagctatattttac tttaagcaat 1920 tcttttattc aaaaaccatt tattaagtgc ccttgcaatatcaatcgctg tgccaggcat 1980 tgaatctaca gatgtgagca agacaaagta cctgtcctcaaggagctcat agtataatga 2040 ggagattaac aagaaaatgt attattacaa tttagtccagtgtcatagca taaggatgat 2100 gcgaggggaa aacccgagca gtgttgccaa gaggaggaaataggccaatg tggtctggga 2160 cggttggata tacttaaaca tcttaataat cagagtaattttcatttaca aagagaggtc 2220 ggtacttaaa ataaccctga aaaataacac tggaattccttttctagcat tatatttatt 2280 cctgatttgc ctttgccata taatctaatg cttgtttatatagtgtctgg tattgtttaa 2340 cagttctgtc ttttctattt aaatgccact aaattttaaattcatacctt tccatgattc 2400 aaaattcaaa agatcccatg ggagatggtt ggaaaatctccacttcatcc tccaagccat 2460 tcaagtttcc tttccagaag caactgctac tgcctttcattcatatgttc ttctaaagat 2520 agtctacatt tggaaatgta tgttaaaagc acgtatttttaaaatttttt tcctaaatag 2580 taacacattg tatgtctgct gtgtactttg ctatttttatttattttagt gtttcttata 2640 tagcagatgg aatgaatttg aagttcccag ggctgaggatccatgccttc tttgtttcta 2700 agttatcttt cccatagctt ttcattatct ttcatatgatccagtatatg ttaaatatgt 2760 cctacatata catttagaca accaccattt gttaagtatttgctctagga cagagtttgg 2820 atttgtttat gtttgctcaa aaggagaccc atgggctctccagggtgcac tgagtcaatc 2880 tagtcctaaa aagcaatctt attattaact ctgtatgacagaatcatgtc tggaactttt 2940 gttttctgct ttctgtcaag tataaacttc actttgatgctgtacttgca aaatcacatt 3000 ttctttctgg aaattccggc agtgtacctt gactgctagctaccctgtgc cagaaaagcc 3060 tcattcgttg tgcttgaacc cttgaatgcc accagctgtcatcactacac agccctccta 3120 agaggcttcc tggaggtttc gagattcaga tgccctgggagatcccagag tttcctttcc 3180 ctcttggcca tattctggtg tcaatgacaa ggagtaccttggctttgcca catgtcaagg 3240 ctgaagaaac agtgtctcca acagagctcc ttgtgttatctgtttgtaca tgtgcatttg 3300 tacagtaatt ggtgtgacag tgttctttgt gtgaattacaggcaagaatt gtggctgagc 3360 aaggcacata gtctactcag tctattccta agtcctaactcctccttgtg gtgttggatt 3420 tgtaaggcac tttatccctt ttgtctcatg tttcatcgtaaatggcatag gcagagatga 3480 tacctaattc tgcatttgat tgtcactttt tgtacctgcattaatttaat aaaatattct 3540 tatttatttt gttacttggt aaaaaaaaaa aaaaa 3575<210> SEQ ID NO 42 <211> LENGTH: 290 <212> TYPE: PRT <213> ORGANISM:Homo sapiens <400> SEQUENCE: 42 Met Arg Ile Phe Ala Val Phe Ile Phe MetThr Tyr Trp His Leu Leu 1 5 10 15 Asn Ala Phe Thr Val Thr Val Pro LysAsp Leu Tyr Val Val Glu Tyr 20 25 30 Gly Ser Asn Met Thr Ile Glu Cys LysPhe Pro Val Glu Lys Gln Leu 35 40 45 Asp Leu Ala Ala Leu Ile Val Tyr TrpGlu Met Glu Asp Lys Asn Ile 50 55 60 Ile Gln Phe Val His Gly Glu Glu AspLeu Lys Val Gln His Ser Ser 65 70 75 80 Tyr Arg Gln Arg Ala Arg Leu LeuLys Asp Gln Leu Ser Leu Gly Asn 85 90 95 Ala Ala Leu Gln Ile Thr Asp ValLys Leu Gln Asp Ala Gly Val Tyr 100 105 110 Arg Cys Met Ile Ser Tyr GlyGly Ala Asp Tyr Lys Arg Ile Thr Val 115 120 125 Lys Val Asn Ala Pro TyrAsn Lys Ile Asn Gln Arg Ile Leu Val Val 130 135 140 Asp Pro Val Thr SerGlu His Glu Leu Thr Cys Gln Ala Glu Gly Tyr 145 150 155 160 Pro Lys AlaGlu Val Ile Trp Thr Ser Ser Asp His Gln Val Leu Ser 165 170 175 Gly LysThr Thr Thr Thr Asn Ser Lys Arg Glu Glu Lys Leu Phe Asn 180 185 190 ValThr Ser Thr Leu Arg Ile Asn Thr Thr Thr Asn Glu Ile Phe Tyr 195 200 205Cys Thr Phe Arg Arg Leu Asp Pro Glu Glu Asn His Thr Ala Glu Leu 210 215220 Val Ile Pro Glu Leu Pro Leu Ala His Pro Pro Asn Glu Arg Thr His 225230 235 240 Leu Val Ile Leu Gly Ala Ile Leu Leu Cys Leu Gly Val Ala LeuThr 245 250 255 Phe Ile Phe Arg Leu Arg Lys Gly Arg Met Met Asp Val LysLys Cys 260 265 270 Gly Ile Gln Asp Thr Asn Ser Lys Lys Gln Ser Asp ThrHis Leu Glu 275 280 285 Glu Thr 290 <210> SEQ ID NO 43 <211> LENGTH: 891<212> TYPE: DNA <213> ORGANISM: Mus musculus <220> FEATURE: <221>NAME/KEY: modified_base <222> LOCATION: all “n” positions <223> OTHERINFORMATION: n=a, c, g, or t <400> SEQUENCE: 43 cgtccgcttg cacgtcgcgggccagtctcc tcgcctgcag atagttccca aaacatgagg 60 atatttgctg gcattatattcacagcctgc tgtcacttgc tacgggcgtt tactatcacg 120 gctccaaagg acttgtacgtggtggagtat ggcagcaacg tcacgatgga gtgcagattc 180 cctgtagaac gggagctggacctgcttgcg ttagtggtgt actgggaaaa ggaagatgag 240 caagtgattc agtttgtggcaggagaggag gaccttaagc ctcagcacag caacttcagg 300 gggagagcct cgctgccaaaggaccagctt ttgaagggaa atgctgccct tcagatcaca 360 gacgtcaagc tgcaggacgcaggcgtttac tgctgcataa tcagctacgg tggtgcggac 420 tacaagcgaa tcacgctggaagtcaatgcc ccataccgca aaatcaacca gagaatttcc 480 gtggatccag ccacttctgagcatgaacta atatgtcagg ccgagggtta tccagaagct 540 gaggtaatct ggacaaacagtgaccaccaa cccgtgagtg ggaagagaag tgtcaccact 600 tcccggacag aggggatgcttctcaatgtg accagcagtc tgaggtcaac gccacatgan 660 nagcgaatga tgtttctactgtacgtattg gagatcacag ccagggcaaa accacacagc 720 ggcganatca tcccagaactgcctgcaaca catcctccac agaacaggac tcactgggtg 780 cttctgggat ccatcctgttgttcctcatt gtagtgtcca cggtcctcct cttcttgaga 840 aaacaagtga gaatgctagatgtggagaaa tgtggcgttg aagatacaag c 891 <210> SEQ ID NO 44 <211> LENGTH:279 <212> TYPE: PRT <213> ORGANISM: Mus musculus <220> FEATURE: <221>NAME/KEY: SITE <222> LOCATION: all “Xaa” positions <223> OTHERINFORMATION: Xaa=unknown amino acid <400> SEQUENCE: 44 Met Arg Ile PheAla Gly Ile Ile Phe Thr Ala Cys Cys His Leu Leu 1 5 10 15 Arg Ala PheThr Ile Thr Ala Pro Lys Asp Leu Tyr Val Val Glu Tyr 20 25 30 Gly Ser AsnVal Thr Met Glu Cys Arg Phe Pro Val Glu Arg Glu Leu 35 40 45 Asp Leu LeuAla Leu Val Val Tyr Trp Glu Lys Glu Asp Glu Gln Val 50 55 60 Ile Gln PheVal Ala Gly Glu Glu Asp Leu Lys Pro Gln His Ser Asn 65 70 75 80 Phe ArgGly Arg Ala Ser Leu Pro Lys Asp Gln Leu Leu Lys Gly Asn 85 90 95 Ala AlaLeu Gln Ile Thr Asp Val Lys Leu Gln Asp Ala Gly Val Tyr 100 105 110 CysCys Ile Ile Ser Tyr Gly Gly Ala Asp Tyr Lys Arg Ile Thr Leu 115 120 125Glu Val Asn Ala Pro Tyr Arg Lys Ile Asn Gln Arg Ile Ser Val Asp 130 135140 Pro Ala Thr Ser Glu His Glu Leu Ile Cys Gln Ala Glu Gly Tyr Pro 145150 155 160 Glu Ala Glu Val Ile Trp Thr Asn Ser Asp His Gln Pro Val SerGly 165 170 175 Lys Arg Ser Val Thr Thr Ser Arg Thr Glu Gly Met Leu LeuAsn Val 180 185 190 Thr Ser Ser Leu Arg Ser Thr Pro His Xaa Xaa Arg MetMet Phe Leu 195 200 205 Leu Tyr Val Leu Glu Ile Thr Ala Arg Ala Lys ProHis Ser Gly Xaa 210 215 220 Ile Ile Pro Glu Leu Pro Ala Thr His Pro ProGln Asn Arg Thr His 225 230 235 240 Trp Val Leu Leu Gly Ser Ile Leu LeuPhe Leu Ile Val Val Ser Thr 245 250 255 Val Leu Leu Phe Leu Arg Lys GlnVal Arg Met Leu Asp Val Glu Lys 260 265 270 Cys Gly Val Glu Asp Thr Ser275 <210> SEQ ID NO 45 <211> LENGTH: 135 <212> TYPE: PRT <213> ORGANISM:Oryctolagus cuniculus <220> FEATURE: <221> NAME/KEY: SITE <222>LOCATION: all “Xaa” positions <223> OTHER INFORMATION: Xaa=unknown aminoacid <400> SEQUENCE: 45 Met Leu Gly Ser Pro Cys Leu Leu Trp Leu Leu AlaVal Thr Phe Leu 1 5 10 15 Val Pro Arg Ala Gln Pro Leu Ala Ser Gln AspSer Glu Glu Glu Gly 20 25 30 Asp Asp Gln Pro Ser Leu Pro Pro Ser Arg AlaVal Pro Cys Asp Tyr 35 40 45 Asp Arg Cys Arg His Leu Gln Val Pro Cys GlnGlu Leu Gln Lys Ala 50 55 60 Glu Pro Val Pro Cys Leu Cys Pro Gly Leu SerSer Pro Asp Gln Pro 65 70 75 80 Pro Glu Pro Pro Arg Leu Gly Glu Val HisVal Val Ala Glu Xaa Gly 85 90 95 Arg Ala Leu Val His Trp Cys Ala Pro SerSer Pro Val Leu Gln Tyr 100 105 110 Trp Leu Leu Leu Trp Glu Xaa Asn GlyAsp Pro Trp Lys Gly Thr Asn 115 120 125 Leu Asn Ala His Gly Pro Gln 130135 <210> SEQ ID NO 46 <211> LENGTH: 52 <212> TYPE: PRT <213> ORGANISM:Homo sapiens <400> SEQUENCE: 46 Lys Thr Ala Leu Gly Glu Leu Leu Lys ProLeu Asn Ser Glu Tyr Gly 1 5 10 15 Lys Val Ala Pro Gly Trp Gly Thr ThrPro Leu Met Gly Val Phe Met 20 25 30 Ala Leu Phe Ala Val Phe Leu Leu IleIle Leu Glu Ile Tyr Asn Ser 35 40 45 Ser Val Leu Leu 50 <210> SEQ ID NO47 <211> LENGTH: 273 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400>SEQUENCE: 47 Met Thr Phe Asp Asp Leu Lys Ile Gln Thr Val Lys Asp Gln ProAsp 1 5 10 15 Glu Lys Ser Asn Gly Lys Lys Ala Lys Gly Leu Gln Phe LeuTyr Ser 20 25 30 Pro Trp Trp Cys Leu Ala Ala Ala Thr Leu Gly Val Leu CysLeu Gly 35 40 45 Leu Val Val Thr Ile Met Val Leu Gly Met Gln Leu Ser GlnVal Ser 50 55 60 Asp Leu Leu Thr Gln Glu Gln Ala Asn Leu Thr His Gln LysLys Lys 65 70 75 80 Leu Glu Gly Gln Ile Ser Ala Arg Gln Gln Ala Glu GluAla Ser Gln 85 90 95 Glu Ser Glu Asn Glu Leu Lys Glu Met Ile Glu Thr LeuAla Arg Lys 100 105 110 Leu Asn Glu Lys Ser Lys Glu Gln Met Glu Leu HisHis Gln Asn Leu 115 120 125 Asn Leu Gln Glu Thr Leu Lys Arg Val Ala AsnCys Ser Ala Pro Cys 130 135 140 Pro Gln Asp Trp Ile Trp His Gly Glu AsnCys Tyr Leu Phe Ser Ser 145 150 155 160 Gly Ser Phe Asn Trp Glu Lys SerGln Glu Lys Cys Leu Ser Leu Asp 165 170 175 Ala Lys Leu Leu Lys Ile AsnSer Thr Ala Asp Leu Asp Phe Ile Gln 180 185 190 Gln Ala Ile Ser Tyr SerSer Phe Pro Phe Trp Met Gly Leu Ser Arg 195 200 205 Arg Asn Pro Ser TyrPro Trp Leu Trp Glu Asp Gly Ser Pro Leu Met 210 215 220 Pro His Leu PheArg Val Arg Gly Ala Val Ser Gln Thr Tyr Pro Ser 225 230 235 240 Gly ThrCys Ala Tyr Ile Gln Arg Gly Ala Val Tyr Ala Glu Asn Cys 245 250 255 IleLeu Ala Ala Phe Ser Ile Cys Gln Lys Lys Ala Asn Leu Arg Ala 260 265 270Gln <210> SEQ ID NO 48 <211> LENGTH: 247 <212> TYPE: PRT <213> ORGANISM:Mus musculus <400> SEQUENCE: 48 Met Leu Leu Leu Leu Pro Ile Leu Asn LeuSer Leu Gln Leu His Pro 1 5 10 15 Val Ala Ala Leu Phe Thr Val Thr AlaPro Lys Glu Val Tyr Thr Val 20 25 30 Asp Val Gly Ser Ser Val Ser Leu GluCys Asp Phe Asp Arg Arg Glu 35 40 45 Cys Thr Glu Leu Glu Gly Ile Arg AlaSer Leu Gln Lys Val Glu Asn 50 55 60 Asp Thr Ser Leu Gln Ser Glu Arg AlaThr Leu Leu Glu Glu Gln Leu 65 70 75 80 Pro Leu Gly Lys Ala Leu Phe HisIle Pro Ser Val Gln Val Arg Asp 85 90 95 Ser Gly Gln Tyr Arg Cys Leu ValIle Cys Gly Ala Ala Trp Asp Tyr 100 105 110 Lys Tyr Leu Thr Val Lys ValLys Ala Ser Tyr Met Arg Ile Asp Thr 115 120 125 Arg Ile Leu Glu Val ProGly Thr Gly Glu Val Gln Leu Thr Cys Gln 130 135 140 Ala Arg Gly Tyr ProLeu Ala Glu Val Ser Trp Gln Asn Val Ser Val 145 150 155 160 Pro Ala AsnThr Ser His Ile Arg Thr Pro Glu Gly Leu Tyr Gln Val 165 170 175 Thr SerVal Leu Arg Leu Lys Pro Gln Pro Ser Arg Asn Phe Ser Cys 180 185 190 MetPhe Trp Asn Ala His Met Lys Glu Leu Thr Ser Ala Ile Ile Asp 195 200 205Pro Leu Ser Arg Met Glu Pro Lys Val Pro Arg Thr Trp Pro Leu His 210 215220 Val Phe Ile Pro Ala Cys Thr Ile Ala Leu Ile Phe Leu Ala Ile Val 225230 235 240 Ile Ile Gln Arg Lys Arg Ile 245 <210> SEQ ID NO 49 <211>LENGTH: 702 <212> TYPE: DNA <213> ORGANISM: Mus musculus <220> FEATURE:<221> NAME/KEY: modified_base <222> LOCATION: all “n” positions <223>OTHER INFORMATION: n=a, c, g, or t <400> SEQUENCE: 49 gcaacaagcggcccaccttc ctgaagatcg agaagccact gtcgtaccgc aagcccatgg 60 acacggacctggtgtacatg gagaagtcgc ccaactactg cgaggaggac ccggtcaccg 120 gcagtgtgggcacccagggc cgcgcctgca acaagacggc tccccaggcc agcggctgtg 180 acctcatgtgctgtgggcgt ggctacaaca cccaccagtc cgcccgcgtg tggcagtgca 240 actgtaagttccactggtgc tgctatgtca agtgcaacac gtgcagcgag cgcacggang 300 atgtacacgtgcaagtgagc cccgtgtgca caccaccctc ccgctgcaag tcagattgct 360 gggaggactggaccgtttcc aagctgcggg ctccctggca ggatgctgcg cttgtctttt 420 ctgctgaggagggtactttt cctgggtttc ctgcaggcat ccgtggggga aaaaaaatct 480 ctcagagncctcaactattc tgttccacac ccaatgctga tccaccctcc cccagacaca 540 gcccaggtccctccgcggct ggagcgaagc cttctgcagc aggaactctg gacccctggg 600 cctcatcacagcaatattta acaatttatt cctgataaaa ataatattaa tttatttaat 660 taaaaagaattcttccaaaa aaaaaaaaaa aaaaaaacnt cg 702 <210> SEQ ID NO 50 <211> LENGTH:15 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 50 SerGlu Arg Ser Asp Arg Val Leu Glu Gly Phe Ile Lys Gly Arg 1 5 10 15

What is claimed is:
 1. An isolated nucleic acid molecule selected fromthe group consisting of: a) a nucleic acid molecule having a nucleotidesequence which is at least 90% identical to the nucleotide sequence ofany of SEQ ID NOs: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27,29, 31, 33, 35, 37, 39, 41, and 43, and the nucleotide sequence of anyof the clones deposited as ATCC® Accession numbers 98999, 98899, 207045,207046, 207222, PTA-34, PTA-34, PTA-224, PTA-293, PTA-292, PTA-295,PTA-294, PTA-424, and PTA-438, or a complement thereof; b) a nucleicacid molecule comprising at least 15 nucleotide residues and having anucleotide sequence identical to at least 15 consecutive nucleotideresidues of any of SEQ ID NOs: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21,23, 25, 27, 29, 31, 33, 35, 37, 39, 41, and 43, and the nucleotidesequence of any of the clones deposited as ATCC® Accession numbers98999, 98899, 207045, 207046, 207222, PTA-34, PTA-34, PTA-224, PTA-293,PTA-292, PTA-295, PTA-294, PTA-424, and PTA-438, or a complementthereof; c) a nucleic acid molecule which encodes a polypeptidecomprising the amino acid sequence of any of SEQ ID NOs: 2, 4, 6, 8, 10,12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, and 44,and the amino acid sequence encoded by the nucleotide sequence of any ofthe clones deposited as ATCC® Accession numbers 98999, 98899, 207045,207046, 207222, PTA-34, PTA-34, PTA-224, PTA-293, PTA-292, PTA-295,PTA-294, PTA-424, and PTA-438; d) a nucleic acid molecule which encodesa fragment of a polypeptide comprising the amino acid sequence of any ofSEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32,34, 36, 38, 40, 42, and 44, and the amino acid sequence encoded by thenucleotide sequence of any of the clones deposited as ATCC® Accessionnumbers 98999, 98899, 207045, 207046, 207222, PTA-34, PTA-34, PTA-224,PTA-293, PTA-292, PTA-295, PTA-294, PTA-424, and PTA-438, wherein thefragment comprises at least 10 consecutive amino acid residues of any ofSEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32,34, 36, 38, 40, 42, and 44, and the amino acid sequence encoded by thenucleotide sequence of any of the clones deposited as ATCC® Accessionnumbers 98999, 98899, 207045, 207046, 207222, PTA-34, PTA-34, PTA-224,PTA-293, PTA-292, PTA-295, PTA-294, PTA-424, and PTA-438; and e) anucleic acid molecule which encodes a fragment of a polypeptidecomprising the amino acid sequence of any of SEQ ID NOs: 2, 4, 6, 8, 10,12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, and 44,and the amino acid sequence encoded by the nucleotide sequence of any ofthe clones deposited as ATCC® Accession numbers 98999, 98899, 207045,207046, 207222, PTA-34, PTA-34, PTA-224, PTA-293, PTA-292, PTA-295,PTA-294, PTA-424, and PTA-438, wherein the fragment comprisesconsecutive amino acid residues corresponding to at least half of thefull length of any of SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20,22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, and 44, and the amino acidsequence encoded by the nucleotide sequence of any of the clonesdeposited as ATCC® Accession numbers 98999, 98899, 207045, 207046,207222, PTA-34, PTA-34, PTA-224, PTA-293, PTA-292, PTA-295, PTA-294,PTA-424, and PTA-438; and f) a nucleic acid molecule which encodes anaturally occurring allelic variant of a polypeptide comprising theamino acid sequence of any of SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16,18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, and 44, wherein thenucleic acid molecule hybridizes with a nucleic acid molecule consistingof the nucleotide sequence of any of SEQ ID NOs: 1, 3, 5, 7, 9, 11, 13,15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, and 43, and thenucleotide sequence of any of the clones deposited as ATCC® Accessionnumbers 98999, 98899, 207045, 207046, 207222, PTA-34, PTA-34, PTA-224,PTA-293, PTA-292, PTA-295, PTA-294, PTA-424, and PTA-438, or acomplement thereof under stringent conditions.
 2. The isolated nucleicacid molecule of claim 1, which is selected from the group consistingof: a) a nucleic acid having the nucleotide sequence of any of SEQ IDNOs: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35,37, 39, 41, and 43, and the nucleotide sequence of any of the clonesdeposited as ATCC® Accession numbers 98999, 98899, 207045, 207046,207222, PTA-34, PTA-34, PTA-224, PTA-293, PTA-292, PTA-295, PTA-294,PTA-424, and PTA-438, or a complement thereof; and b) a nucleic acidmolecule which encodes a polypeptide having the amino acid sequence ofany of SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28,30, 32, 34, 36, 38, 40, 42, and 44, and the amino acid sequence encodedby the nucleotide sequence of any of the clones deposited as ATCC®Accession numbers 98999, 98899, 207045, 207046, 207222, PTA-34, PTA-34,PTA-224, PTA-293, PTA-292, PTA-295, PTA-294, PTA-424, and PTA-438, or acomplement thereof.
 3. The nucleic acid molecule of claim 1, furthercomprising vector nucleic acid sequences.
 4. The nucleic acid moleculeof claim 1 further comprising nucleic acid sequences encoding aheterologous polypeptide.
 5. A host cell which contains the nucleic acidmolecule of claim
 1. 6. The host cell of claim 5 which is a mammalianhost cell.
 7. A non-human mammalian host cell containing the nucleicacid molecule of claim
 1. 8. An isolated polypeptide selected from thegroup consisting of: a) a fragment of a polypeptide comprising the aminoacid sequence of any of SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20,22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, and 44, and the amino acidsequence encoded by the nucleotide sequence of any of the clonesdeposited as ATCC® Accession numbers 98999, 98899, 207045, 207046,207222, PTA-34, PTA-34, PTA-224, PTA-293, PTA-292, PTA-295, PTA-294,PTA-424, and PTA-438; b) a naturally occurring allelic variant of apolypeptide comprising the amino acid sequence of any of SEQ ID NOs: 2,4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40,42, and 44, wherein the polypeptide is encoded by a nucleic acidmolecule which hybridizes with a nucleic acid molecule consisting of thenucleotide sequence of any of SEQ ID NOs: 1, 3, 5, 7, 9, 11, 13, 15, 17,19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, and 43, and thenucleotide sequence of any of the clones deposited as ATCC® Accessionnumbers 98999, 98899, 207045, 207046, 207222, PTA-34, PTA-34, PTA-224,PTA-293, PTA-292, PTA-295, PTA-294, PTA-424, and PTA-438, or acomplement thereof under stringent conditions; and c) a polypeptidewhich is encoded by a nucleic acid molecule comprising a nucleotidesequence which is at least 90% identical to a nucleic acid consisting ofthe nucleotide sequence of any of SEQ ID NOs: 1, 3, 5, 7, 9, 11, 13, 15,17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, and 43, and thenucleotide sequence of any of the clones deposited as ATCC® Accessionnumbers 98999, 98899, 207045, 207046, 207222, PTA-34, PTA-34, PTA-224,PTA-293, PTA-292, PTA-295, PTA-294, PTA-424, and PTA-438, or acomplement thereof.
 9. The isolated polypeptide of claim 8 having theamino acid sequence of any of SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16,18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, and 44, and theamino acid sequence encoded by the nucleotide sequence of any of theclones deposited as ATCC® Accession numbers 98999, 98899, 207045,207046, 207222, PTA-34, PTA-34, PTA-224, PTA-293, PTA-292, PTA-295,PTA-294, PTA-424, and PTA-438.
 10. The polypeptide of claim 8, whereinthe amino acid sequence of the polypeptide further comprisesheterologous amino acid residues.
 11. An antibody which selectivelybinds with the polypeptide of claim
 8. 12. A method for producing apolypeptide selected from the group consisting of: a) a polypeptidecomprising the amino acid sequence of any of SEQ ID NOs: 2, 4, 6, 8, 10,12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, and 44,and the amino acid sequence encoded by the nucleotide sequence of any ofthe clones deposited as ATCC® Accession numbers 98999, 98899, 207045,207046, 207222, PTA-34, PTA-34, PTA-224, PTA-293, PTA-292, PTA-295,PTA-294, PTA-424, and PTA-438; b) a polypeptide comprising a fragment ofthe amino acid sequence of any of SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14,16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, and 44, and theamino acid sequence encoded by the nucleotide sequence of any of theclones deposited as ATCC® Accession numbers 98999, 98899, 207045,207046, 207222, PTA-34, PTA-34, PTA-224, PTA-293, PTA-292, PTA-295,PTA-294, PTA-424, and PTA-438, wherein the fragment comprises at least10 contiguous amino acids of any of SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14,16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, and 44, and theamino acid sequence encoded by the nucleotide sequence of any of theclones deposited as ATCC® Accession numbers 98999, 98899, 207045,207046, 207222, PTA-34, PTA-34, PTA-224, PTA-293, PTA-292, PTA-295,PTA-294, PTA-424, and PTA-438; and c) a naturally occurring allelicvariant of a polypeptide comprising the amino acid sequence of any ofSEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32,34, 36, 38, 40, 42, 44, or a complement thereof, wherein the polypeptideis encoded by a nucleic acid molecule which hybridizes with a nucleicacid molecule consisting of the nucleotide sequence of any of SEQ IDNOs: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35,37, 39, 41, and 43, and the nucleotide sequence of any of the clonesdeposited as ATCC® Accession numbers 98999, 98899, 207045, 207046,207222, PTA-34, PTA-34, PTA-224, PTA-293, PTA-292, PTA-295, PTA-294,PTA-424, and PTA-438, or a complement thereof under stringentconditions; the method comprising culturing the host cell of claim 5under conditions in which the nucleic acid molecule is expressed.
 13. Amethod for detecting the presence of a polypeptide of claim 8 in asample, comprising: a) contacting the sample with a compound whichselectively binds with a polypeptide of claim 8; and b) determiningwhether the compound binds with the polypeptide in the sample.
 14. Themethod of claim 13, wherein the compound which binds with thepolypeptide is an antibody.
 15. A kit comprising a compound whichselectively binds with a polypeptide of claim 8 and instructions foruse.
 16. A method for detecting the presence of a nucleic acid moleculeof claim 1 in a sample, comprising the steps of: a) contacting thesample with a nucleic acid probe or primer which selectively hybridizeswith the nucleic acid molecule; and b) determining whether the nucleicacid probe or primer binds with a nucleic acid molecule in the sample.17. The method of claim 16, wherein the sample comprises mRNA moleculesand is contacted with a nucleic acid probe.
 18. A kit comprising acompound which selectively hybridizes with a nucleic acid molecule ofclaim 1 and instructions for use.
 19. A method for identifying acompound which binds with a polypeptide of claim 8 comprising the stepsof: a) contacting a polypeptide, or a cell expressing a polypeptide ofclaim 8 with a test compound; and b) determining whether the polypeptidebinds with the test compound.
 20. The method of claim 19, wherein thebinding of the test compound to the polypeptide is detected by a methodselected from the group consisting of: a) detection of binding by directdetecting of test compound/polypeptide binding; b) detection of bindingusing a competition binding assay; c) detection of binding using anassay for an activity characteristic of the polypeptide.
 21. A methodfor modulating the activity of a polypeptide of claim 8 comprisingcontacting a polypeptide or a cell expressing a polypeptide of claim 8with a compound which binds with the polypeptide in a sufficientconcentration to modulate the activity of the polypeptide.
 22. A methodfor identifying a compound which modulates the activity of a polypeptideof claim 8, comprising: a) contacting a polypeptide of claim 8 with atest compound; and b) determining the effect of the test compound on theactivity of the polypeptide to thereby identify a compound whichmodulates the activity of the polypeptide.
 23. An antibody substancewhich selectively binds with the polypeptide of claim
 8. 24. A method ofmaking an antibody substance which selectively binds with thepolypeptide of claim 8, the method comprising providing the polypeptideto an immunocompetent vertebrate and thereafter harvesting from thevertebrate blood or serum comprising the antibody substance.
 25. Amethod of making an antibody substance which selectively binds with thepolypeptide of claim 8, the method comprising contacting the polypeptidewith a plurality of particles which individually comprise an antibodysubstance and a nucleic acid encoding the antibody substance,segregating a particle which selectively binds with the polypeptide, andexpressing the antibody substance from the nucleic acid of thesegregated particle.
 26. The isolated nucleic acid of claim 1, whereinthe isolated nucleic acid comprises a portion having the nucleotidesequence of one of SEQ ID NOs: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21,23, 25, 27, 29, 31, 33, 35, 37, 39, 41, and
 43. 27. The isolatedpolypeptide of claim 8, wherein the amino acid sequence of the isolatedpolypeptide is one of SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20,22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, and 44.